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Liu H, Bui Q, Hassenstab J, Gordon BA, Benzinger TLS, Timsina J, Sung YJ, Karch C, Renton AE, Daniels A, Morris JC, Xiong C, Ibanez L, Perrin RJ, Llibre‐Guerra JJ, Day GS, Supnet‐Bell C, Xu X, Berman SB, Chhatwal JP, Ikeuchi T, Kasuga K, Niimi Y, Huey ED, Schofield PR, Brooks WS, Ryan NS, Jucker M, Laske C, Levin J, Vöglein J, Roh JH, Lopera F, Bateman RJ, Cruchaga C, McDade EM, For DIAN study team. Ubiquitin-proteasome system in the different stages of dominantly inherited Alzheimer's disease. Alzheimers Dement 2025; 21:e70243. [PMID: 40411302 PMCID: PMC12102666 DOI: 10.1002/alz.70243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/31/2025] [Accepted: 04/07/2025] [Indexed: 05/26/2025]
Abstract
INTRODUCTION This study investigated the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins. METHOD The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale. RESULTS Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS-activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late-stage tau biomarkers, microglia, and axonal degeneration. DISCUSSION The rise in UPS proteins alongside tau-related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD. HIGHLIGHTS This study investigates the ubiquitin-proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late-stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau-pathology-driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.
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Affiliation(s)
- Haiyan Liu
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Quoc Bui
- Department of BiostatisticsWashington University in St. LouisSt. LouisMissouriUSA
| | - Jason Hassenstab
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Brian A. Gordon
- Department of RadiologyWashington University in St. LouisSt. LouisMissouriUSA
| | | | - Jigyasha Timsina
- Department of PsychiatryWashington University in St. LouisSt. LouisMissouriUSA
| | - Yun Ju Sung
- Department of PsychiatryWashington University in St. LouisSt. LouisMissouriUSA
| | - Celeste Karch
- Department of PsychiatryWashington University in St. LouisSt. LouisMissouriUSA
| | - Alan E. Renton
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Alisha Daniels
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - John C. Morris
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Chengjie Xiong
- Department of BiostatisticsWashington University in St. LouisSt. LouisMissouriUSA
| | - Laura Ibanez
- Department of PsychiatryWashington University in St. LouisSt. LouisMissouriUSA
| | - Richard J. Perrin
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
- Department of Pathology and ImmunologyWashington University in St. LouisSt. LouisMissouriUSA
| | | | - Gregory S. Day
- Department of NeurologyMayo Clinic in FloridaJacksonvilleFloridaUSA
| | | | - Xiong Xu
- Department of BiostatisticsWashington University in St. LouisSt. LouisMissouriUSA
| | - Sarah B. Berman
- Departments of Neurology and Clinical & Translational ScienceUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Jasmeer P. Chhatwal
- Brigham and Women's Hospital, Massachusetts General HospitalHarvard Medical SchoolCambridgeMassachusettsUSA
| | | | | | - Yoshiki Niimi
- Specially appointed lecturer, Unit for Early and Exploratory Clinical DevelopmentThe University of TokyoTokyoJapan
| | - Edward D. Huey
- Memory and Aging Program, Butler Hospital, Department of Psychiatry and Human Behavior, Alpert Medical SchoolBrown UniversityProvidenceRhode IslandUSA
| | - Peter R. Schofield
- Neuroscience Research AustraliaSydneyNew South WalesAustralia
- Faculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
| | - William S. Brooks
- Neuroscience Research AustraliaSydneyNew South WalesAustralia
- Faculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
| | - Natalie S. Ryan
- Dementia Research CentreUCL Queen Square Institute of NeurologyLondonUK
- UK Dementia Research Institute at UCLLondonUK
| | - Mathias Jucker
- German Center for Neurodegenerative Diseases (DZNE) TübingenTübingenGermany
- Section for Dementia Research, Hertie Institute for Clinical Brain Research, Department of Psychiatry and PsychotherapyUniversity of TübingenTübingenGermany
| | - Christoph Laske
- German Center for Neurodegenerative Diseases (DZNE) TübingenTübingenGermany
- Section for Dementia Research, Hertie Institute for Clinical Brain Research, Department of Psychiatry and PsychotherapyUniversity of TübingenTübingenGermany
| | - Johannes Levin
- German Center for Neurodegenerative DiseasesSite MunichMunichGermany
- Department of NeurologyLudwig‐Maximilians‐Universität MünchenMunichGermany
- Munich Cluster for Systems Neurology (SyNergy)MunichGermany
| | - Jonathan Vöglein
- Munich Cluster for Systems Neurology (SyNergy)MunichGermany
- Department of NeurologyLMU University HospitalLMU MunichMunichGermany
- German Center for Neurodegenerative Diseases (DZNE)MunichGermany
| | - Jee Hoon Roh
- Departments of Neurology and PhysiologyKorea University Anam HospitalKorea University College of MedicineSeoulSouth Korea
| | - Francisco Lopera
- Grupo de Neurociencias de Antioquia (GNA), Facultad de MedicinaUniversidad de AntioquiaMedellínColombia
| | - Randall J. Bateman
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Carlos Cruchaga
- Department of PsychiatryWashington University in St. LouisSt. LouisMissouriUSA
| | - Eric M. McDade
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
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Church TR, Margolis SS. Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease. Front Cell Dev Biol 2025; 12:1531797. [PMID: 39990094 PMCID: PMC11842346 DOI: 10.3389/fcell.2024.1531797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 12/23/2024] [Indexed: 02/25/2025] Open
Abstract
Neurodegenerative diseases are characterized by the progressive breakdown of neuronal structure and function and the pathological accumulation of misfolded protein aggregates and toxic protein oligomers. A major contributor to the deterioration of neuronal physiology is the disruption of protein catabolic pathways mediated by the proteasome, a large protease complex responsible for most cellular protein degradation. Previously, it was believed that proteolysis by the proteasome required tagging of protein targets with polyubiquitin chains, a pathway called the ubiquitin-proteasome system (UPS). Because of this, most research on proteasomal roles in neurodegeneration has historically focused on the UPS. However, additional ubiquitin-independent pathways and their importance in neurodegeneration are increasingly recognized. In this review, we discuss the range of ubiquitin-independent proteasome pathways, focusing on substrate identification and targeting, regulatory molecules and adaptors, proteasome activators and alternative caps, and diverse proteasome complexes including the 20S proteasome, the neuronal membrane proteasome, the immunoproteasome, extracellular proteasomes, and hybrid proteasomes. These pathways are further discussed in the context of aging, oxidative stress, protein aggregation, and age-associated neurodegenerative diseases, with a special focus on Alzheimer's Disease, Huntington's Disease, and Parkinson's Disease. A mechanistic understanding of ubiquitin-independent proteasome function and regulation in neurodegeneration is critical for the development of therapies to treat these devastating conditions. This review summarizes the current state of ubiquitin-independent proteasome research in neurodegeneration.
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Affiliation(s)
- Taylor R. Church
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Seth S. Margolis
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Desouky MA, Michel HE, Elsherbiny DA, George MY. Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation. Life Sci 2024; 359:123206. [PMID: 39489397 DOI: 10.1016/j.lfs.2024.123206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/30/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators.
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Affiliation(s)
- Mahmoud A Desouky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566 Cairo, Egypt
| | - Haidy E Michel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566 Cairo, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566 Cairo, Egypt
| | - Mina Y George
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566 Cairo, Egypt.
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Zuniga NR, Earls NE, Denos AEA, Elison JM, Jones BS, Smith EG, Moran NG, Broce KL, Romero GM, Hyer CD, Wagstaff KB, Almughamsi HM, Transtrum MK, Price JC. Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain. PLoS Comput Biol 2024; 20:e1012407. [PMID: 39666759 DOI: 10.1371/journal.pcbi.1012407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/26/2024] [Accepted: 11/03/2024] [Indexed: 12/14/2024] Open
Abstract
Apolipoprotein E (ApoE) polymorphisms modify the risk of Alzheimer's disease with ApoE4 strongly increasing and ApoE2 modestly decreasing risk relative to the control ApoE3. To investigate how ApoE isoforms alter risk, we measured changes in proteome homeostasis in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). The regulation of each protein's homeostasis is observed by measuring turnover rate and abundance for that protein. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, lack of cohesion between mitochondrial membrane and matrix proteins suggests that dysregulation of proteasome and autophagy is reducing protein quality. In ApoE2, proteins of the mitochondrial matrix and the membrane, including oxidative phosphorylation complexes, had a similar increase in degradation which suggests coordinated replacement of the entire organelle. In the liver we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.
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Affiliation(s)
- Nathan R Zuniga
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Noah E Earls
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Ariel E A Denos
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Jared M Elison
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Benjamin S Jones
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Ethan G Smith
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Noah G Moran
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Katie L Broce
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Gerome M Romero
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Chad D Hyer
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Kimberly B Wagstaff
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - Haifa M Almughamsi
- Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia
| | - Mark K Transtrum
- Department of Physics and Astronomy, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
| | - John C Price
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, Utah, United States of America
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Tana M, Piccinini R, Moffa L, Tana C. Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart. Int J Mol Sci 2024; 25:11519. [PMID: 39519069 PMCID: PMC11546592 DOI: 10.3390/ijms252111519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Heart Failure with Preserved Ejection Fraction (HFpEF) is one of the most frequent causes of heart failure in the world's population (about 19-55%), and is commonly associated with a high rate of hospitalization (almost 70-80%) and with increased mortality (40-50% in a 5-year timeframe). The elderly are more often affected, with higher rates of hospitalizations than young people, and currently almost 70% of the population aged 65 years old has HFpEF. An increase in cardiomyocyte stiffness, thus resulting in diastolic dysfunction, increased filling pressures and heart failure with preserved ejection fraction are characteristics features of the disease. In addition, among the various causes of HFpEF, cardiac amyloidosis (CA) can provoke diastolic dysfunction and increased wall stiffness directly from intercellular deposition of insoluble proteic substances and their toxic activity. Totally, almost 30 different proteins are able to form deposits, but the most frequently involved are transthyretin and misfolded monoclonal immunoglobulin light chains, which bring to two clinical conditions called transthyretin amyloidosis (ATTR) and light-chain amyloidosis (AL). Although there has been increasing attention on ATTR-CA in recent years, the actual prevalence remains underestimated, especially in people of advanced age, as well as its real impact as a cause of HFpEF, and only data derived from autoptic exams are currently available. Moreover, CA itself often mimics HFpEF, and some conflicting data on the use of predictive scores are described in the literature. The close relationship between HFpEF and CA, especially in older population and the main pathophysiological mechanisms which bond these two conditions are described in this focused review. The need to screen red flags for ATTR-CA in elderly patients with HFpEF is urgently advised, because a prompt recognition of the disease can optimize the approach to the disease with an early therapeutic, life-saving choice.
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Affiliation(s)
- Marco Tana
- Internal Medicine and Cardiovascular Ultrasound Unit, Medical Department, SS. Annunziata Hospital, 66100 Chieti, Italy
- School of Internal Medicine, Faculty of Medicine, G. D’Annunzio University, 66100 Chieti, Italy
| | - Rachele Piccinini
- School of Internal Medicine, Faculty of Medicine, G. D’Annunzio University, 66100 Chieti, Italy
| | - Livia Moffa
- School of Internal Medicine, Faculty of Medicine, G. D’Annunzio University, 66100 Chieti, Italy
| | - Claudio Tana
- Geriatric Clinic, SS. Annunziata Hospital, 66100 Chieti, Italy
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Colussi C, Bertozzi A, Leone L, Rinaudo M, Sollazzo R, Conte F, Paccosi E, Nardella L, Aceto G, Li Puma DD, Ripoli C, Vita MG, Marra C, D'Ascenzo M, Grassi C. Nucleoporin 153 deficiency in adult neural stem cells defines a pathological protein-network signature and defective neurogenesis in a mouse model of AD. Stem Cell Res Ther 2024; 15:275. [PMID: 39227892 PMCID: PMC11373261 DOI: 10.1186/s13287-024-03805-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 06/17/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer's disease (AD), contributing to progressive memory loss and cognitive decline. Reduced levels of the nucleoporin 153 (Nup153), a key epigenetic regulator of NSC stemness, characterize the neural stem cells isolated from a mouse model of AD (3×Tg) (AD-NSCs) and determine their altered plasticity and gene expression. METHODS Nup153-regulated mechanisms contributing to NSC function were investigated: (1) in cultured NSCs isolated from AD and wild type (WT) mice by proteomics; (2) in vivo by lentiviral-mediated delivery of Nup153 or GFP in the hippocampus of AD and control mice analyzing neurogenesis and cognitive function; (3) in human iPSC-derived brain organoids obtained from AD patients and control subjects as a model of neurodevelopment. RESULTS Proteomic approach identified Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. Gene ontology (GO) analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism, nuclear import and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration, mitochondrial dysfunction, proteasomal processing and RNA degradation. Furthermore, recovery of Nup153 levels in AD-NSCs reduced the levels of oxidative stress markers and recovered proteasomal activity. Lentiviral-mediated delivery of Nup153 in the hippocampal niche of AD mice increased the proliferation of early progenitors, marked by BrdU/DCX and BrdU/PSANCAM positivity and, later, the integration of differentiating neurons in the cell granule layer (BrdU/NeuN+ cells) compared with GFP-injected AD mice. Consistently, Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD-GFP mice at 1 month after virus delivery assessed by Morris Water Maze. To validate the role of Nup153 in neurogenesis we took advantage of brain organoids derived from AD-iPSCs characterized by fewer neuroepithelial progenitor loops and reduced differentiation areas. The upregulation of Nup153 in AD organoids recovered the formation of neural-like tubes and differentiation. CONCLUSIONS Our data suggest that the positive effect of Nup153 on neurogenesis is based on a complex regulatory network orchestrated by Nup153 and that this protein is a valuable disease target.
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Affiliation(s)
- Claudia Colussi
- Istituto di Analisi dei Sistemi ed Informatica "Antonio Ruberti" (IASI) - CNR , National Research Council, Via dei Taurini 19, Rome, 00185, Italy.
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.
| | - Alessia Bertozzi
- Istituto di Analisi dei Sistemi ed Informatica "Antonio Ruberti" (IASI) - CNR , National Research Council, Via dei Taurini 19, Rome, 00185, Italy
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
| | - Lucia Leone
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Marco Rinaudo
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Raimondo Sollazzo
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
| | - Federica Conte
- Istituto di Analisi dei Sistemi ed Informatica "Antonio Ruberti" (IASI) - CNR , National Research Council, Via dei Taurini 19, Rome, 00185, Italy
| | - Elena Paccosi
- Istituto di Analisi dei Sistemi ed Informatica "Antonio Ruberti" (IASI) - CNR , National Research Council, Via dei Taurini 19, Rome, 00185, Italy
| | - Luca Nardella
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
| | - Giuseppe Aceto
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Domenica Donatella Li Puma
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Cristian Ripoli
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | | | - Camillo Marra
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Marcello D'Ascenzo
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
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Hossen F, Sun GY, Lee JC. Oligomeric Tau-induced oxidative damage and functional alterations in cerebral endothelial cells: Role of RhoA/ROCK signaling pathway. Free Radic Biol Med 2024; 221:261-272. [PMID: 38815773 PMCID: PMC11184584 DOI: 10.1016/j.freeradbiomed.2024.05.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/22/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
Despite of yet unknown mechanism, microvascular deposition of oligomeric Tau (oTau) has been implicated in alteration of the Blood-Brain Barrier (BBB) function in Alzheimer's disease (AD) brains. In this study, we employed an in vitro BBB model using primary mouse cerebral endothelial cells (CECs) to investigate the mechanism underlying the effects of oTau on BBB function. We found that exposing CECs to oTau induced oxidative stress through NADPH oxidase, increased oxidative damage to proteins, decreased proteasome activity, and expressions of tight junction (TJ) proteins including occludin, zonula occludens-1 (ZO-1) and claudin-5. These effects were suppressed by the pretreatment with Fasudil, a RhoA/ROCK signaling inhibitor. Consistent with the biochemical alterations, we found that exposing the basolateral side of CECs to oTau in the BBB model disrupted the integrity of the BBB, as indicated by an increase in FITC-dextran transport across the model, and a decrease in trans endothelial electrical resistance (TEER). oTau also increased the transmigration of peripheral blood mononuclear cells (PBMCs) in the BBB model. These functional alterations in the BBB induced by oTau were also suppressed by Fasudil. Taken together, our findings suggest that targeting the RhoA/ROCK pathway can be a potential therapeutic strategy to maintain BBB function in AD.
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Affiliation(s)
- Faruk Hossen
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL, 60607, USA
| | - Grace Y Sun
- Biochemistry Department, University of Missouri, Columbia, MO, 65211, USA
| | - James C Lee
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL, 60607, USA.
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Zuniga NR, Earls NE, Denos AEA, Elison JM, Jones BS, Smith EG, Moran NG, Brown KL, Romero GM, Hyer CD, Wagstaff KB, Almughamsi HM, Transtrum MK, Price JC. Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.13.607719. [PMID: 39185235 PMCID: PMC11343127 DOI: 10.1101/2024.08.13.607719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Apolipoprotein E (ApoE) polymorphisms modify the risk of neurodegenerative disease with the ApoE4 isoform increasing and ApoE2 isoform decreasing risk relative to the 'wild-type control' ApoE3 isoform. To elucidate how ApoE isoforms alter the proteome, we measured relative protein abundance and turnover in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). This data provides insight into how ApoE isoforms affect the in vivo synthesis and degradation of a wide variety of proteins. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, this regulation is not cohesive suggesting that aerobic respiration is impacted by proteasomal and autophagic dysregulation. ApoE2 mice exhibited a matching change in mitochondrial matrix proteins and the membrane which suggests coordinated maintenance of the entire organelle. In the liver, we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.
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Affiliation(s)
- Nathan R. Zuniga
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Noah E. Earls
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Ariel E. A. Denos
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Jared M. Elison
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Benjamin S. Jones
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Ethan G. Smith
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Noah G. Moran
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Katie L. Brown
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Gerome M. Romero
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Chad D. Hyer
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Kimberly B. Wagstaff
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - Haifa M. Almughamsi
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
- Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia
| | - Mark K. Transtrum
- Department of Physics and Astronomy, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
| | - John C. Price
- Department of Chemistry and Biochemistry, College of Computational, Physical, and Mathematical Sciences, Brigham Young University, Provo, UT, USA
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9
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Bartkowiak-Wieczorek J, Malesza M, Malesza I, Hadada T, Winkler-Galicki J, Grzelak T, Mądry E. Methylsulfinyl Hexyl Isothiocyanate (6-MSITC) from Wasabi Is a Promising Candidate for the Treatment of Cancer, Alzheimer's Disease, and Obesity. Nutrients 2024; 16:2509. [PMID: 39125389 PMCID: PMC11313713 DOI: 10.3390/nu16152509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Methylsulfinyl hexyl isothiocyanate (6-MSITC) isolated from Eutrema japonicum is a promising candidate for the treatment of breast cancer, colorectal and stomach cancer, metabolic syndrome, heart diseases, diabetes, and obesity due to its anti-inflammatory and antioxidant properties. Also, its neuroprotective properties, improving cognitive function and protecting dopaminergic neurons, make it an excellent candidate for treating neurodegenerative diseases like dementia, Alzheimer's, and Parkinson's disease. 6-MSITC acts on many signaling pathways, such as PPAR, AMPK, PI3K/AKT/mTOR, Nrf2/Keap1-ARE, ERK1/2-ELK1/CHOP/DR5, and MAPK. However, despite the very promising results of in vitro and in vivo animal studies and a few human studies, the molecule has not yet been thoroughly tested in the human population. Nonetheless, wasabi should be classified as a "superfood" for the primary and secondary prevention of human diseases. This article reviews the current state-of-the-art research on 6-MSITC and its potential clinical uses, discussing in detail the signaling pathways activated by the molecule and their interactions.
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Affiliation(s)
- Joanna Bartkowiak-Wieczorek
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
| | - Michał Malesza
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
| | - Ida Malesza
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Tomasz Hadada
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
| | - Jakub Winkler-Galicki
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
| | - Teresa Grzelak
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
| | - Edyta Mądry
- Physiology Department, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznan, Poland; (M.M.); (T.H.); (J.W.-G.); (T.G.); (E.M.)
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10
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McDade E, Liu H, Bui Q, Hassenstab J, Gordon B, Benzinger T, Shen Y, Timsina J, Wang L, Sung YJ, Karch C, Renton A, Daniels A, Morris J, Xiong C, Ibanez L, Perrin R, Llibre-Guerra JJ, Day G, Supnet-Bell C, Xu X, Berman S, Chhatwal J, Ikeuchi T, Kasuga K, Niimi Y, Huey E, Schofield P, Brooks W, Ryan N, Jucker M, Laske C, Levin J, Vöglein J, Roh JH, Lopera F, Bateman R, Cruchaga C. Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer's Disease. RESEARCH SQUARE 2024:rs.3.rs-4202125. [PMID: 39108475 PMCID: PMC11302696 DOI: 10.21203/rs.3.rs-4202125/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Alan Renton
- Nash Family Department of Neuroscience and Ronald Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA: Departments of Neurology and Genetics and Ge
| | | | | | | | | | | | | | | | | | | | | | - Jasmeer Chhatwal
- Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School
| | | | - Kensaku Kasuga
- Department of Molecular Genetics, Brain Research Institute, Niigata University
| | | | | | | | | | | | | | | | | | | | | | | | - Randall Bateman
- Department of Neurology, Washington University School of Medicine
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11
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Ren Q, Fu J, Duan X, Sun L, Mu Z, Liang W, Li Y, Wang Z, Xiu S. The Effects of Ketogenic Diet on Brain Gene Expressions in Type 2 Diabetes Background. Neuroscience 2024; 549:101-109. [PMID: 38734303 DOI: 10.1016/j.neuroscience.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/07/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a major risk factor of a number of neurodegenerative diseases (NDDs). Ketogenic diet (KD) has significant beneficial effects on glycemic control and may act effectively against NDDs, but the mechanism remains unclear. In this study, we aimed to investigate the potential effects of KD on gene expressions in the brains of T2DM model mice. Male db/db mice at the age of 9 weeks were fed with KD or normal diet to the age of 6 months, and the whole brains were subjected to mRNA-seq analysis for differentially expressed genes. KD significantly lowered fasting glucose and body weights in db/db mice (P < 0.05), and the expression of 189 genes in the brain were significantly changed (P < 0.05, |log2| > 1). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the differentially expressed genes upon KD are involved in inflammatory responses and the functions of biosynthesis. In inflammatory responses, NF-κB signaling pathway, viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction pathways were enriched, and in biosynthesis pathways, genes functioning in lipid and amino acid metabolism, protein synthesis, and energy metabolism were enriched. Moreover, consistent with the gene set enrichment analysis results, proteasomal activity measured biochemically were enhanced in KD-fed T2DM mice. These data may facilitate the understanding of how KD can be protective to the brain in T2DM background. KD could be a new strategy for the prevention of NDDs in T2DM patients.
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Affiliation(s)
- Qianxu Ren
- The National Clinical Research Center for Geriatric Disease, Department of Neurology, Advanced Innovation Center for Human Brain Protection, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Junling Fu
- Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Xiaoye Duan
- Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Lina Sun
- Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Zhijing Mu
- Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wenping Liang
- The National Clinical Research Center for Geriatric Disease, Department of Neurology, Advanced Innovation Center for Human Brain Protection, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yu Li
- The National Clinical Research Center for Geriatric Disease, Department of Neurology, Advanced Innovation Center for Human Brain Protection, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhe Wang
- The National Clinical Research Center for Geriatric Disease, Department of Neurology, Advanced Innovation Center for Human Brain Protection, Xuanwu Hospital, Capital Medical University, Beijing, China.
| | - Shuangling Xiu
- Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
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12
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Zheng Y, Wang C, Liu W, Chen J, Sun Y, Chang D, Wang H, Xu W, Lu JJ, Zhou X, Huang M. Upregulation of Nrf2 signaling: A key molecular mechanism of Baicalin's neuroprotective action against diabetes-induced cognitive impairment. Biomed Pharmacother 2024; 174:116579. [PMID: 38631145 DOI: 10.1016/j.biopha.2024.116579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND AND AIM Diabetes-associated cognitive impairment (DCI) is a prevalent complication of diabetes. However, there is a lack of viable strategies for preventing and treating DCI. This study aims to explore the efficacy of baicalin (Bai) in attenuating DCI and elucidating the underlying mechanisms. EXPERIMENTAL PROCEDURE GK rats fed a high-fat and high-glucose diet were utilized to investigate the therapeutic potential of Bai. Cognitive function was assessed using the Morris water maze and novel object recognition tests. To gain insight into the molecular mechanisms underlying Bai's neuro-protective effects, co-cultured BV2/HT22 cells were established under high-glucose (HG) stimulation. The modes of action of Bai were subsequently confirmed in vivo using the DCI model in db/db mice. KEY RESULTS Bai restored cognitive and spatial memory and attenuated neuron loss, along with reducing expressions of Aβ and phosphorylated Tau protein in diabetic GK rats. At the cellular level, Bai exhibited potent antioxidant and anti-inflammatory effects against HG stimulation. These effects were associated with the upregulation of Nrf2 and supressed Keap1 levels. Consistent with these in vitro findings, similar mechanisms were observed in db/db mice. The significant neuroprotective effects of Bai were abolished when co-administered with ATRA, a Nrf2 blocker, in db/db mice, confirming that KEAP1-Nrf2 signaling pathway was responsible for the observed effect. CONCLUSIONS AND IMPLICATIONS Bai demonstrates a great therapeutic potential for attenuating DCI. The antioxidant defense and anti-inflammatory actions of Bai were mediated through the KEAP1-Nrf2 axis. These findings advance our understanding of potential treatment approaches for DCI, a common complication associated with diabetes.
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Affiliation(s)
- Yanfang Zheng
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Chenxiang Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Wenjing Liu
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Jiaying Chen
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Yibin Sun
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia
| | - Huan Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Wen Xu
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China.
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia.
| | - Mingqing Huang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China.
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13
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Halliwell B. Understanding mechanisms of antioxidant action in health and disease. Nat Rev Mol Cell Biol 2024; 25:13-33. [PMID: 37714962 DOI: 10.1038/s41580-023-00645-4] [Citation(s) in RCA: 152] [Impact Index Per Article: 152.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2023] [Indexed: 09/17/2023]
Abstract
Several different reactive oxygen species (ROS) are generated in vivo. They have roles in the development of certain human diseases whilst also performing physiological functions. ROS are counterbalanced by an antioxidant defence network, which functions to modulate ROS levels to allow their physiological roles whilst minimizing the oxidative damage they cause that can contribute to disease development. This Review describes the mechanisms of action of antioxidants synthesized in vivo, antioxidants derived from the human diet and synthetic antioxidants developed as therapeutic agents, with a focus on the gaps in our current knowledge and the approaches needed to close them. The Review also explores the reasons behind the successes and failures of antioxidants in treating or preventing human disease. Antioxidants may have special roles in the gastrointestinal tract, and many lifestyle features known to promote health (especially diet, exercise and the control of blood glucose and cholesterol levels) may be acting, at least in part, by antioxidant mechanisms. Certain reactive sulfur species may be important antioxidants but more accurate determinations of their concentrations in vivo are needed to help assess their contributions.
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Affiliation(s)
- Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Neurobiology Research Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore, Singapore.
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14
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Abidi SMS, Sharma C, Randhawa S, Shukla AK, Acharya A. A review on nanotechnological perspective of "the amyloid cascade hypothesis" for neurodegenerative diseases. Int J Biol Macromol 2023; 253:126821. [PMID: 37690655 DOI: 10.1016/j.ijbiomac.2023.126821] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/12/2023]
Abstract
Neurodegenerative diseases (NDs) are characterized by progressive degeneration of neurons which deteriorates the brain functions. An early detection of the onset of NDs is utmost important, as it will provide the fast treatment strategies to prevent further progression of the disease. Conventionally, accurate diagnosis of the brain related disorders is difficult in their early phase. To solve this problem, nanotechnology based neurofunctional imaging and biomarker detection techniques have been developed which allows high specificity and sensitivity towards screening and diagnosis of NDs. Another challenge to treat the brain related disorders is to overcome the complex integrity of blood-brain-barrier (BBB) for the delivery of theranostic agents. Fortunately, utilization of nanomaterials has been pursued as promising strategy to address this challenge. Herein, we critically highlighted the recent improvements in the field of neurodiagnostic and therapeutic approaches involving innovative strategies for diagnosis, and inhibition of protein aggregates. We have provided particular emphasis on the use of nanotechnology which can push forward the blooming research growth in this field to win the battle against devastating NDs.
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Affiliation(s)
- Syed M S Abidi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Chandni Sharma
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shiwani Randhawa
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ashish K Shukla
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amitabha Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
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15
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Jiang Y, MacNeil LT. Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies. Mol Neurodegener 2023; 18:82. [PMID: 37950311 PMCID: PMC10638731 DOI: 10.1186/s13024-023-00664-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 10/04/2023] [Indexed: 11/12/2023] Open
Abstract
The lack of effective therapies that slow the progression of Alzheimer's disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular pathways regulating proteostasis and stress response in these organisms facilitates the study of genetic factors that contribute to, or protect against, neurodegeneration. Here, we review genetic modifiers of neurodegeneration and related cellular pathways identified in the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, focusing on models of AD and related tauopathies. We further address the potential of simple model systems to better understand the fundamental mechanisms that lead to AD and other neurodegenerative disorders.
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Affiliation(s)
- Yuwei Jiang
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
| | - Lesley T MacNeil
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada.
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada.
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16
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Walker CK, Greathouse KM, Tuscher JJ, Dammer EB, Weber AJ, Liu E, Curtis KA, Boros BD, Freeman CD, Seo JV, Ramdas R, Hurst C, Duong DM, Gearing M, Murchison CF, Day JJ, Seyfried NT, Herskowitz JH. Cross-Platform Synaptic Network Analysis of Human Entorhinal Cortex Identifies TWF2 as a Modulator of Dendritic Spine Length. J Neurosci 2023; 43:3764-3785. [PMID: 37055180 PMCID: PMC10198456 DOI: 10.1523/jneurosci.2102-22.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/17/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023] Open
Abstract
Proteomic studies using postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer's disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex (EC) of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry (MS) data (n = 2260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (BA28; n = 58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.SIGNIFICANCE STATEMENT Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex (EC) samples spanning cognitively normal and Alzheimer's disease (AD) cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 (TWF2) as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.
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Affiliation(s)
- Courtney K Walker
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Kelsey M Greathouse
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jennifer J Tuscher
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Eric B Dammer
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Audrey J Weber
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Evan Liu
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Kendall A Curtis
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Benjamin D Boros
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Cameron D Freeman
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jung Vin Seo
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Raksha Ramdas
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Cheyenne Hurst
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Duc M Duong
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Marla Gearing
- Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Charles F Murchison
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jeremy J Day
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Jeremy H Herskowitz
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
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17
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Türker F, Bharadwaj RA, Kleinman JE, Weinberger DR, Hyde TM, White CJ, Williams DW, Margolis SS. Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue. J Biol Chem 2023:104811. [PMID: 37172721 DOI: 10.1016/j.jbc.2023.104811] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/20/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally adapted. Here, we describe pitfalls and define straightforward orthogonal biochemical approaches essential to measure and understand changes in proteasome composition and activity in the mammalian central nervous system. Through our experimentation in the mammalian brain, we determined an abundance of catalytically active proteasomes exist with and without a 19S cap(s), the regulatory particle essential for ubiquitin-dependent degradation. Moreover, we learned that in-cell measurements using activity-based probes (ABPs) are more sensitive in determining the available activity of the 20S proteasome without the 19S cap and in measuring individual catalytic subunit activities of each β subunit within all neuronal proteasomes. Subsequently, applying these tools to human brain samples, we were surprised to find that post-mortem tissue retained little to no 19S-capped proteasome, regardless of age, sex, or disease state. Comparing brain tissues (parahippocampal gyrus) from human Alzheimer's disease (AD) patients and unaffected subjects, available 20S proteasome activity was significantly elevated in severe cases of AD, an observation not previously noted. Taken together, our study establishes standardized approaches for comprehensive investigation of proteasomes in mammalian brain tissue, and we reveal new insight into brain proteasome biology.
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Affiliation(s)
- Fulya Türker
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Rahul A Bharadwaj
- The Lieber Institute for Brain Development, Baltimore, MD 21205, USA
| | - Joel E Kleinman
- The Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Daniel R Weinberger
- The Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Thomas M Hyde
- The Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Cory J White
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Dionna W Williams
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA; Department of Molecular Microbiology & Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Seth S Margolis
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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18
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Mi Z, Graham SH. Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury. Ageing Res Rev 2023; 86:101856. [PMID: 36681249 PMCID: PMC9992267 DOI: 10.1016/j.arr.2023.101856] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/15/2023] [Indexed: 01/20/2023]
Abstract
UCHL1 is a multifunctional protein expressed at high concentrations in neurons in the brain and spinal cord. UCHL1 plays important roles in regulating the level of cellular free ubiquitin and redox state as well as the degradation of select proteins. This review focuses on the potential role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury and recovery. Subjects addressed in the review include 1) Normal physiological functions of UCHL1. 2) Posttranslational modification sites and splice variants that alter the function of UCHL1 and mouse models with mutations and deletions of UCHL1. 3) The hypothesized role and pathogenic mechanisms of UCHL1 in neurodegenerative diseases and brain injury. 4) Potential therapeutic strategies targeting UCHL1 in these disorders.
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Affiliation(s)
- Zhiping Mi
- Departments of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, United States.
| | - Steven H Graham
- Departments of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, United States.
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19
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JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model. Cells 2023; 12:cells12060904. [PMID: 36980245 PMCID: PMC10047857 DOI: 10.3390/cells12060904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/10/2023] [Accepted: 03/12/2023] [Indexed: 03/18/2023] Open
Abstract
The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology.
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20
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Bermejo-Bescós P, Jiménez-Aliaga KL, Benedí J, Martín-Aragón S. A Diet Containing Rutin Ameliorates Brain Intracellular Redox Homeostasis in a Mouse Model of Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24054863. [PMID: 36902309 PMCID: PMC10003355 DOI: 10.3390/ijms24054863] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Quercetin has been studied extensively for its anti-Alzheimer's disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and rutin on intracellular redox homeostasis of the brain (reduced glutathione/oxidized glutathione, GSH/GSSG), its correlation with β-site APP cleaving enzyme 1 (BACE1) activity, and amyloid precursor protein (APP) expression in transgenic TgAPP mice (bearing human Swedish mutation APP transgene, APPswe). On the basis that BACE1 protein and APP processing are regulated by the ubiquitin-proteasome pathway and that supplementation with GSH protects neurons from proteasome inhibition, we investigated whether a diet containing quercetin or rutin (30 mg/kg/day, 4 weeks) diminishes several early signs of AD. Genotyping analyses of animals were carried out by PCR. In order to determine intracellular redox homeostasis, spectrofluorometric methods were adopted to quantify GSH and GSSG levels using o-phthalaldehyde and the GSH/GSSG ratio was ascertained. Levels of TBARS were determined as a marker of lipid peroxidation. Enzyme activities of SOD, CAT, GR, and GPx were determined in the cortex and hippocampus. ΒACE1 activity was measured by a secretase-specific substrate conjugated to two reporter molecules (EDANS and DABCYL). Gene expression of the main antioxidant enzymes: APP, BACE1, a Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), caspase-3, caspase-6, and inflammatory cytokines were determined by RT-PCR. First, overexpression of APPswe in TgAPP mice decreased GSH/GSSG ratio, increased malonaldehyde (MDA) levels, and, overall, decreased the main antioxidant enzyme activities in comparison to wild-type (WT) mice. Treatment of TgAPP mice with quercetin or rutin increased GSH/GSSG, diminished MDA levels, and favored the enzyme antioxidant capacity, particularly with rutin. Secondly, both APP expression and BACE1 activity were diminished with quercetin or rutin in TgAPP mice. Regarding ADAM10, it tended to increase in TgAPP mice with rutin treatment. As for caspase-3 expression, TgAPP displayed an increase which was the opposite with rutin. Finally, the increase in expression of the inflammatory markers IL-1β and IFN-γ in TgAPP mice was lowered by both quercetin and rutin. Collectively, these findings suggest that, of the two flavonoids, rutin may be included in a day-to-day diet as a form of adjuvant therapy in AD.
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21
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Ma X, Feng Y, Quan X, Geng B, Li G, Fu X, Zeng L. Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer's disease. Front Genet 2023; 13:967730. [PMID: 36704351 PMCID: PMC9871314 DOI: 10.3389/fgene.2022.967730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 12/07/2022] [Indexed: 01/12/2023] Open
Abstract
Chaperonin containing TCP1 subunit 2 (CCT2) is essential in various neurodegenerative diseases, albeit its role in the pathogenesis of Alzheimer's disease (AD) remains elusive. This study aimed to evaluate the role of CCT2 in Alzheimer's disease. First, bioinformatics database analysis revealed that CCT2 was significantly downregulated in patients with Alzheimer's disease and associated with autophagic clearance of β-amyloid. The 789 differentially expressed genes overlapped in AD-group and CCT2-low/high group, and the CCT2-high-associated genes screened by Pearson coefficients were enriched in protein folding, autophagy, and messenger RNA stability regulation pathways. These results suggest that CCT2 is significantly and positively associated with multiple pathways linked to autophagy and negatively associated with neuronal death. The logistic prediction model with 13 key genes, such as CCT2, screened in this study better predicts Alzheimer's disease occurrence (AUC = 0.9671) and is a favorable candidate for predicting potential biological targets of Alzheimer's disease. Additionally, this study predicts reciprocal micro RNAs and small molecule drugs for hub genes. Our findings suggest that low CCT2 expression may be responsible for the autophagy suppression in Alzheimer's disease, providing an accurate explanation for its pathogenesis and new targets and small molecule inhibitors for its treatment.
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Affiliation(s)
- Xueting Ma
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Yuxin Feng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Xiangyu Quan
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Bingyu Geng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Guodong Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Xueqi Fu
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Linlin Zeng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China,*Correspondence: Linlin Zeng,
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22
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Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients. Sci Rep 2022; 12:17675. [PMID: 36319674 PMCID: PMC9626495 DOI: 10.1038/s41598-022-21796-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022] Open
Abstract
A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55-90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21-all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers-four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy-even with abundant co-morbidity.
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23
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Jurcău MC, Andronie-Cioara FL, Jurcău A, Marcu F, Ţiț DM, Pașcalău N, Nistor-Cseppentö DC. The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer's Disease: Therapeutic Implications and Future Perspectives. Antioxidants (Basel) 2022; 11:2167. [PMID: 36358538 PMCID: PMC9686795 DOI: 10.3390/antiox11112167] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/28/2022] [Accepted: 10/29/2022] [Indexed: 08/26/2023] Open
Abstract
Alzheimer's disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.
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Affiliation(s)
| | - Felicia Liana Andronie-Cioara
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Anamaria Jurcău
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Florin Marcu
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Delia Mirela Ţiț
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Nicoleta Pașcalău
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Delia Carmen Nistor-Cseppentö
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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24
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Farag MA, Hariri MLM, Ehab A, Homsi MN, Zhao C, von Bergen M. Cocoa seeds and chocolate products interaction with gut microbiota; mining microbial and functional biomarkers from mechanistic studies, clinical trials and 16S rRNA amplicon sequencing. Crit Rev Food Sci Nutr 2022; 64:3122-3138. [PMID: 36190306 DOI: 10.1080/10408398.2022.2130159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
In recent years, gut microbiome has evolved as a focal point of interest with growing recognition that a well-balanced gut microbiota is highly relevant to an individual's health status. The present review provides a mechanistic insight on the effects of cocoa chemicals on the gut microbiome and further reveals in silico biomarkers, taxonomic and functional features that distinguish gut microbiome of cocoa consumers and controls by using 16S rRNA gene sequencing data. The polyphenols in cocoa can change the gut microbiota either by inhibiting the growth of pathogenic bacteria in the gut such as Clostridium perfringens or by increasing the growth of beneficial microbiota in the gut such as Lactobacillus and Bifidobacterium. This paper demonstrates the holistic effect of gut microbiota on cocoa chemicals and how it impacts human health. We present herein the first comprehensive review and analysis of how raw and roasted cocoa and its products can specifically influence gut homeostasis, and likewise, how microbiota metabolizes cocoa chemicals. In addition to that, our 16S rRNA amplicon sequencing analysis revealed that the flavone and flavonols metabolism, aminobenzoate degradation and fatty acid elongation pathways represent the three most important signatures of microbial functions associated with cocoa consumption.
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Affiliation(s)
- Mohamed A Farag
- Department of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Mohamad Louai M Hariri
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, New Cairo, Egypt
| | - Aya Ehab
- Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, New Cairo, Egypt
| | - Masun Nabhan Homsi
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Chao Zhao
- College of Marine Sciences, Fujian Agricultural and Forestry University, Fuzhou, China
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fuzhou, China
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
- Institute of Biochemistry, Life Science Faculty, University of Leipzig, Leipzig, Germany
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
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25
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Zuo J, Zhang Z, Luo M, Zhou L, Nice EC, Zhang W, Wang C, Huang C. Redox signaling at the crossroads of human health and disease. MedComm (Beijing) 2022; 3:e127. [PMID: 35386842 PMCID: PMC8971743 DOI: 10.1002/mco2.127] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 02/06/2023] Open
Abstract
Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double-edged sword in disease progression suggest two different therapeutic strategies to treat redox-relevant diseases, in which targeting ROS sources and redox-related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox-relevant diseases.
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Affiliation(s)
- Jing Zuo
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Maochao Luo
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Wei Zhang
- West China Biomedical Big Data CenterWest China HospitalSichuan UniversityChengduP. R. China
- Mental Health Center and Psychiatric LaboratoryThe State Key Laboratory of BiotherapyWest China Hospital of Sichuan UniversityChengduP. R. China
| | - Chuang Wang
- Department of PharmacologyProvincial Key Laboratory of Pathophysiology, Ningbo University School of MedicineNingboZhejiangP. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for BiotherapyChengduP. R. China
- Department of PharmacologyProvincial Key Laboratory of Pathophysiology, Ningbo University School of MedicineNingboZhejiangP. R. China
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26
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Physiological Overview of the Potential Link between the UPS and Ca2+ Signaling. Antioxidants (Basel) 2022; 11:antiox11050997. [PMID: 35624861 PMCID: PMC9137615 DOI: 10.3390/antiox11050997] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 02/04/2023] Open
Abstract
The ubiquitin–proteasome system (UPS) is the main proteolytic pathway by which damaged target proteins are degraded after ubiquitination and the recruit of ubiquitinated proteins, thus regulating diverse physiological functions and the maintenance in various tissues and cells. Ca2+ signaling is raised by oxidative or ER stress. Although the basic function of the UPS has been extensively elucidated and has been continued to define its mechanism, the precise relationship between the UPS and Ca2+ signaling remains unclear. In the present review, we describe the relationship between the UPS and Ca2+ signaling, including Ca2+-associated proteins, to understand the end point of oxidative stress. The UPS modulates Ca2+ signaling via the degradation of Ca2+-related proteins, including Ca2+ channels and transporters. Conversely, the modulation of UPS is driven by increases in the intracellular Ca2+ concentration. The multifaceted relationship between the UPS and Ca2+ plays critical roles in different tissue systems. Thus, we highlight the potential crosstalk between the UPS and Ca2+ signaling by providing an overview of the UPS in different organ systems and illuminating the relationship between the UPS and autophagy.
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27
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Chiricosta L, D’Angiolini S, Gugliandolo A, Mazzon E. Artificial Intelligence Predictor for Alzheimer’s Disease Trained on Blood Transcriptome: The Role of Oxidative Stress. Int J Mol Sci 2022; 23:ijms23095237. [PMID: 35563628 PMCID: PMC9104709 DOI: 10.3390/ijms23095237] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Alzheimer’s disease (AD) is an incurable neurodegenerative disease diagnosed by clinicians through healthcare records and neuroimaging techniques. These methods lack sensitivity and specificity, so new antemortem non-invasive strategies to diagnose AD are needed. Herein, we designed a machine learning predictor based on transcriptomic data obtained from the blood of AD patients and individuals without dementia (non-AD) through an 8 × 60 K microarray. The dataset was used to train different models with different hyperparameters. The support vector machines method allowed us to reach a Receiver Operating Characteristic score of 93% and an accuracy of 89%. High score levels were also achieved by the neural network and logistic regression methods. Furthermore, the Gene Ontology enrichment analysis of the features selected to train the model along with the genes differentially expressed between the non-AD and AD transcriptomic profiles shows the “mitochondrial translation” biological process to be the most interesting. In addition, inspection of the KEGG pathways suggests that the accumulation of β-amyloid triggers electron transport chain impairment, enhancement of reactive oxygen species and endoplasmic reticulum stress. Taken together, all these elements suggest that the oxidative stress induced by β-amyloid is a key feature trained by the model for the prediction of AD with high accuracy.
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28
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Manukyan AL. Noise as a cause of neurodegenerative disorders: molecular and cellular mechanisms. Neurol Sci 2022; 43:2983-2993. [PMID: 35166975 DOI: 10.1007/s10072-022-05948-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/08/2022] [Indexed: 12/21/2022]
Abstract
Noise as an environmental stressor becomes of increasing importance in our industrialized world, and especially traffic noise from the environment represents a potential novel neurodegenerative risk factor, as well as for hearing loss. A significant number of studies have been suggested that the overproduction of reactive oxygen species (ROS) has a complex role in stimulation of pathologic events. Experimental studies upon molecular pathways of traffic noise exposure proposed that it increased the level of stress hormones and mediated the inflammatory and oxidative stress (OS) pathways resulting in endothelial and neuronal dysfunction. Studies have shown that neurons are especially sensitive to OS due to high polyunsaturated fatty acids content in membranes, high oxygen uptake, and weak antioxidant defense. However, OS induces the necrotic and apoptotic cell deaths in the cochlea. Chronic noise is one of the many overall reasons of obtained sensorineural hearing loss which destroys cognitive functions in human and animals, as well as suppresses neurogenesis in the hippocampus. Nevertheless, behavioral disorders caused by noise are mainly accompanied with oxidative stress, but the clear molecular mechanism of neurodegeneration due to disruption of the pro- and antioxidant systems is still not fully understood. This paper aims to highlight the down-stream pathophysiology of noise-induced mental disorders, including hearing loss, annoyance, anxiety, depression, memory loss, and Alzheimer's disease, describing the underlying mechanisms of induction of inflammation and oxidative stress.
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Affiliation(s)
- Ashkhen L Manukyan
- Department of Medical Chemistry, Yerevan State Medical University after M. Heratsi, Koryun 2, 0025, Yerevan, Armenia.
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29
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Checler F, Alves da Costa C. Parkin as a Molecular Bridge Linking Alzheimer’s and Parkinson’s Diseases? Biomolecules 2022; 12:biom12040559. [PMID: 35454148 PMCID: PMC9026546 DOI: 10.3390/biom12040559] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 02/01/2023] Open
Abstract
Alzheimer’s (AD) and Parkinson’s (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes and is generally accompanied by ER stress disturbance, autophagic and mitophagic defects, mitochondrial structure and function alterations and enhanced neuronal cell death. Genetic approaches aimed at identifying molecular triggers responsible for familial forms of AD or PD have helped to understand the etiology of their sporadic counterparts. It appears that several proteins thought to contribute to one of these pathologies are also likely to contribute to the other. One such protein is parkin (PK). Here, we will briefly describe anatomical lesions and genetic advances linked to AD and PD as well as the main cellular processes commonly affected in these pathologies. Further, we will focus on current studies suggesting that PK could well participate in AD and thereby act as a molecular bridge between these two pathologies. In particular, we will focus on the transcription factor function of PK and its newly described transcriptional targets that are directly related to AD- and PD-linked cellular defects.
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30
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Huffels CFM, Osborn LM, Hulshof LA, Kooijman L, Henning L, Steinhäuser C, Hol EM. Amyloid-β plaques affect astrocyte Kir4.1 protein expression but not function in the dentate gyrus of APP/PS1 mice. Glia 2022; 70:748-767. [PMID: 34981861 PMCID: PMC9306581 DOI: 10.1002/glia.24137] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 01/09/2023]
Abstract
Alzheimer pathology is accompanied by astrogliosis. Reactive astrocytes surrounding amyloid plaques may directly affect neuronal communication, and one of the mechanisms by which astrocytes impact neuronal function is by affecting K+ homeostasis. Here we studied, using hippocampal slices from 9‐month‐old Alzheimer mice (APP/PS1) and wild‐type littermates, whether astrocyte function is changed by analyzing Kir4.1 expression and function and astrocyte coupling in astrocytes surrounding amyloid‐β plaques. Immunohistochemical analysis of Kir4.1 protein in the dentate gyrus revealed localized increases in astrocytes surrounding amyloid‐β plaque deposits. We subsequently focused on changes in astrocyte function by using patch‐clamp slice electrophysiology on both plaque‐ and non‐plaque associated astrocytes to characterize general membrane properties. We found that Ba2+‐sensitive Kir4.1 conductance in astrocytes surrounding plaques was not affected by changes in Kir4.1 protein expression. Additional analysis of astrocyte gap junction coupling efficiency in the dentate gyrus revealed no apparent changes. Quantification of basic features of glutamatergic transmission to granule cells did not indicate disturbed neuronal communication in the dentate gyrus of APP/PS1 mice. Together, these results suggest that astrocytes in the dentate gyrus of APP/PS1 mice maintain their ability to buffer extracellular K+ and attempt to rectify imbalances in K+ concentration to maintain normal neuronal and synaptic function, possibly by localized increases in Kir4.1 protein expression. Our earlier transcriptomic data indicated that chronically activated astrocytes lose their neuronal support function. Here we show that, despite localized increased Kir4.1 protein expression, astrocyte Kir4.1 channel dysfunction is likely not involved in the pathogenesis of Alzheimer's disease.
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Affiliation(s)
- Christiaan F. M. Huffels
- Department of Translational Neuroscience, University Medical Center Utrecht Brain CenterUtrecht UniversityUtrechtThe Netherlands
| | - Lana M. Osborn
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Lianne A. Hulshof
- Department of Translational Neuroscience, University Medical Center Utrecht Brain CenterUtrecht UniversityUtrechtThe Netherlands
| | - Lieneke Kooijman
- Swammerdam Institute for Life Sciences, Center for NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Lukas Henning
- Institute of Cellular Neurosciences, Medical FacultyUniversity of BonnBonnGermany
| | | | - Elly M. Hol
- Department of Translational Neuroscience, University Medical Center Utrecht Brain CenterUtrecht UniversityUtrechtThe Netherlands
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Li N, Zhan X. Integrated genomic analysis of proteasome alterations across 11,057 patients with 33 cancer types: clinically relevant outcomes in framework of 3P medicine. EPMA J 2021; 12:605-627. [PMID: 34956426 DOI: 10.1007/s13167-021-00256-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/16/2021] [Indexed: 12/30/2022]
Abstract
Relevance Proteasome, a cylindrical complex containing 19S regulatory particle lid, 19S regulatory particle base, and 20S core particle, acted as a major mechanism to regulate the levels of intracellular proteins and degrade misfolded proteins, which involved in many cellular processes, and played important roles in cancer biological processes. Elucidation of proteasome alterations across multiple cancer types will directly contribute to cancer medical services in the context of predictive, preventive, and personalized medicine (PPPM / 3P medicine). Purpose This study aimed to investigate proteasome gene alterations across 33 cancer types for discovery of effective biomarkers and therapeutic targets in the framework of PPPM practice in cancers. Methods Proteasome gene data, including gene expression RNAseq, somatic mutation, tumor mutation burden (TMB), copy number variant (CNV), microsatellite instability (MSI) score, clinical characteristics, immune phenotype, 22 immune cells, cancer stemness index, drug sensitivity, and related pathways, were systematically analyzed with publically available database and bioinformatics across 11,057 patients with 33 cancer types. Results Differentially expressed proteasome genes were extensively found between tumor and control tissues. PSMB4 occurred the top mutation event among proteasome genes, and those proteasome genes were significantly associated with TMB and MSI score. Most of proteasome genes were positively related to CNV among single deletion, control copy number, and single gain. Kaplan-Meier curves and COX regression survival analysis showed proteasome genes were significantly associated with patient survival rate across 33 cancer types. Furthermore, the expressions of proteasome genes were significantly different among different clinical stages and immune subtypes. The expressions of proteasome genes were correlated with immune-related scores (ImmuneScore, StromalScore, and ESTIMATEScore), 22 immune cells, and cancer stemness. The sensitivities of multiple drugs were closely related to proteasome gene expressions. The identified proteasome and proteasome-interacted proteins were significantly enriched in various cancer-related pathways. Conclusions This study provided the first landscape of proteasome alterations across 11,057 patients with 33 cancer types and revealed that proteasome played a significant and wide functional role in cancer biological processes. These findings are the precious scientific data to reveal the common and specific alterations of proteasome genes among 33 cancer types, which benefits the research and practice of PPPM in cancers. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-021-00256-z.
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Affiliation(s)
- Na Li
- Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong 250117 People's Republic of China.,Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, Shandong 250117 People's Republic of China
| | - Xianquan Zhan
- Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong 250117 People's Republic of China.,Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, Shandong 250117 People's Republic of China.,Gastroenterology Research Institute and Clinical Center, Shandong First Medical University, 38 Wuying Shan Road, Jinan, Shandong 250031 People's Republic of China
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Yang X, Guan Y, Yan B, Xie Y, Zhou M, Wu Y, Yao L, Qiu X, Yan F, Chen Y, Huang L. Evidence-based complementary and alternative medicine bioinformatics approach through network pharmacology and molecular docking to determine the molecular mechanisms of Erjing pill in Alzheimer's disease. Exp Ther Med 2021; 22:1252. [PMID: 34539848 PMCID: PMC8438686 DOI: 10.3892/etm.2021.10687] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 01/19/2021] [Indexed: 11/06/2022] Open
Abstract
Erjing pill, a Traditional Chinese Medicine (TCM) formulation composed of Polygonatum sibiricum and Lycium chinense, has an important role in the treatment of Alzheimer's disease (AD). However, the underlying mechanisms of the action of Erjing pill in AD have remained elusive. In the present study, the key ingredients of Erjing pill were investigated and the active components and their mechanisms of action on AD were analyzed based on networks pharmacology. By using the TCM and TCM Systems Pharmacology and databases, the components of Erjing pill were screened and the data were captured using Discovery Studio. The SwissTarget webserver database was used to predict the potential protein targets of Erjing pill components for pathologies related to AD. The data were further analyzed with the disease targets of AD based on analysis of the Online Mendelian Inheritance in Man, DiGSeE and Therapeutic Target Database. Subsequent analysis of mechanistic pathways of the screened components and protein targets allowed us to construct a network by using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, which revealed potential molecular mechanisms of Erjing pill against AD. Finally, the protective effect of three active components on neurons was verified using an in vitro injury model of PC12 cells induced by Aβ25-35. The results indicated that 65 bioactive components of Erjing pill, including lauric acid and zederone, and 6 targets, including acetylcholinesterase, butylcholinesterase and amyloid protein precursor, were closely associated with the prevention and treatment of AD. The molecular components of Erjing pill were indicated to be involved in various biological signaling processes, mainly in synaptic signal transmission, transsynaptic signal transmission and chemical synaptic transmission. Furthermore, related pathways targeted by Erjing pill in AD included the regulation of neuroactive ligand-receptor interactions, the PI3K-Akt signaling pathway, serotoninergic synapses, calcium signaling pathways and dopaminergic synapses. A cell viability assay indicated that the compounds (polygonatine A, polygonatine C and 4',5-dihydroxyflavone) assessed were able to significantly improve the survival rate and increase the Ca2+ level in a PC12 cell model of AD induced by amyloid-β25-35. The present study revealed that the mechanisms of action of Erjing pill to prevent and treat AD included a multicompound, multitarget and multipathway regulatory network.
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Affiliation(s)
- Xiyang Yang
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
| | - Yang Guan
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
| | - Bo Yan
- Department of Research and Development, Shandong Qidu Pharmaceutical Co., Ltd., Zibo, Shandong 255400, P.R. China
| | - Yongyan Xie
- Department of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 333004, P.R. China
| | - Maofu Zhou
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
| | - Yi Wu
- Department of Jiangxi Provincial Institute for Drug Control, Jiangxi Provincial Engineering Research Center for Drug and Medical Device Quality, Nanchang, Jiangxi 330006, P.R. China
| | - Lihua Yao
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
- Department of Life Science, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, P.R. China
| | - Xiaopeng Qiu
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
| | - Feixia Yan
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
| | - Yaohui Chen
- Department of Nephrology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Liping Huang
- Department of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China
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Puigoriol-Illamola D, Companys-Alemany J, McGuire K, Homer NZM, Leiva R, Vázquez S, Mole DJ, Griñán-Ferré C, Pallàs M. Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice. Pharmaceuticals (Basel) 2021; 14:ph14101040. [PMID: 34681264 PMCID: PMC8540242 DOI: 10.3390/ph14101040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/28/2021] [Accepted: 10/08/2021] [Indexed: 11/16/2022] Open
Abstract
Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer's disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes-as well as pro-inflammatory mediators-through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD.
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Affiliation(s)
- Dolors Puigoriol-Illamola
- Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (D.P.-I.); (J.C.-A.); (C.G.-F.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig Vall d’Hebron 171, 08028 Barcelona, Spain
| | - Júlia Companys-Alemany
- Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (D.P.-I.); (J.C.-A.); (C.G.-F.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig Vall d’Hebron 171, 08028 Barcelona, Spain
| | - Kris McGuire
- MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (K.M.); (D.J.M.)
| | - Natalie Z. M. Homer
- Mass Spectrometry Core, Edinburgh Clinical Research Facility, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK;
| | - Rosana Leiva
- Medicinal Chemistry Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (R.L.); (S.V.)
| | - Santiago Vázquez
- Medicinal Chemistry Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (R.L.); (S.V.)
| | - Damian J. Mole
- MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK; (K.M.); (D.J.M.)
| | - Christian Griñán-Ferré
- Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (D.P.-I.); (J.C.-A.); (C.G.-F.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig Vall d’Hebron 171, 08028 Barcelona, Spain
| | - Mercè Pallàs
- Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain; (D.P.-I.); (J.C.-A.); (C.G.-F.)
- Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig Vall d’Hebron 171, 08028 Barcelona, Spain
- Correspondence: ; Tel.: +34-4024531
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Wang H, Zhang Y, Zheng C, Yang S, Chen X, Wang H, Gao S. A 3-Gene-Based Diagnostic Signature in Alzheimer's Disease. Eur Neurol 2021; 85:6-13. [PMID: 34521086 DOI: 10.1159/000518727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/25/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a chronic neurodegenerative disease. In this study, potential diagnostic biomarkers were identified for AD. METHODS All AD samples and healthy samples were collected from 2 datasets in the GEO database, in which differentially expressed genes (DEGs) were analyzed by using the limma package of R language. GO and KEGG pathway enrichment was conducted basing on the DEGs via the clusterProfiler package of R. And, the PPI network construction and gene prediction were performed using the STRING database and Cytoscape. Then, a logistic regression model was constructed to predict the sample type. RESULTS Bioinformatic analysis of GEO datasets revealed 2,063 and 108 DEGs in GSE5281 and GSE4226 datasets, separately, and 15 overlapping DEGs were found. GO and KEGG enrichment analysis revealed terms associated with neurodevelopment. Then, we built a logistic regression model based on the hub genes from the PPI network and optimized the model to 3 genes (ALDOA, ENC1, and NFKBIA). The values of area under the curve of the training set GSE5281 and testing set GSE4226 were 0.9647 and 0.7857, respectively, which implied the efficacy of this model. CONCLUSION The comprehensive bioinformatic analysis of gene expression in AD patients and the effective logistic regression model built in our study may provide promising research value for diagnostic methods of AD.
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Affiliation(s)
- Huimin Wang
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China
| | - Yanqiu Zhang
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China
| | - Chengyao Zheng
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China
| | - Songqi Yang
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China
| | - Xiuju Chen
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China
| | - Heng Wang
- Department of Neurology, Tianjin NanKai Hospital, Tianjin, China,
| | - Sheng Gao
- Department of General Practice, Tianjin NanKai Hospital, Tianjin, China.,Nankai University, Tianjin, China
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Carlyle BC, Kandigian SE, Kreuzer J, Das S, Trombetta BA, Kuo Y, Bennett DA, Schneider JA, Petyuk VA, Kitchen RR, Morris R, Nairn AC, Hyman BT, Haas W, Arnold SE. Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics. Neurobiol Aging 2021; 105:99-114. [PMID: 34052751 PMCID: PMC8338777 DOI: 10.1016/j.neurobiolaging.2021.04.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/18/2021] [Accepted: 04/14/2021] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is defined by the presence of abundant amyloid-β (Aβ) and tau neuropathology. While this neuropathology is necessary for AD diagnosis, it is not sufficient for causing cognitive impairment. Up to one third of community dwelling older adults harbor intermediate to high levels of AD neuropathology at death yet demonstrate no significant cognitive impairment. Conversely, there are individuals who exhibit dementia with no gross explanatory neuropathology. In prior studies, synapse loss correlated with cognitive impairment. To understand how synaptic composition changes in relation to neuropathology and cognition, multiplexed liquid chromatography mass-spectrometry was used to quantify enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting levels of AD pathology and cognitive performance. 123 unique proteins were significantly associated with diagnostic category. Functional analysis showed enrichment of serotonin release and oxidative phosphorylation categories in normal (cognitively unimpaired, low neuropathology) and "resilient" (unimpaired despite AD pathology) individuals. In contrast, frail individuals, (low pathology, impaired cognition) showed a metabolic shift towards glycolysis and increased presence of proteasome subunits.
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Affiliation(s)
- Becky C Carlyle
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA.
| | - Savannah E Kandigian
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Johannes Kreuzer
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA
| | - Sudeshna Das
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Bianca A Trombetta
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Yikai Kuo
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Cardiology Division, Charlestown, MA, USA
| | | | | | | | - Robert R Kitchen
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Cardiology Division, Charlestown, MA, USA
| | - Robert Morris
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA
| | | | - Bradley T Hyman
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Wilhelm Haas
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA
| | - Steven E Arnold
- Massachusetts General Hospital Department of Neurology, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA
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Mohammadnejad A, Baumbach J, Li W, Lund J, Larsen MJ, Li S, Mengel-From J, Michel TM, Christiansen L, Christensen K, Hjelmborg J, Tan Q. Differential lncRNA expression profiling of cognitive function in middle and old aged monozygotic twins using generalized association analysis. J Psychiatr Res 2021; 140:197-204. [PMID: 34118637 DOI: 10.1016/j.jpsychires.2021.05.074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 05/18/2021] [Accepted: 05/29/2021] [Indexed: 12/14/2022]
Abstract
Cognitive impairment is the most prominent symptom in neurodegenerative disorders affecting quality of life and mortality. However, despite years of research, the molecular mechanism underlying the regulation of cognitive function and its impairment is poorly understood. This study aims to elucidate the role of long non-coding RNAs (lncRNAs) expression and lncRNA-mRNA interaction networks, by analyzing lncRNA expression in whole blood samples of 400 middle and old aged monozygotic twins in association with cognitive function using both linear models and a generalized correlation coefficient (GCC) to capture the diverse patterns of correlation. We detected 13 probes (p < 1e-03) displaying nonlinear and 7 probes (p < 1e-03) showing linear correlations. After combining the results, we identified 20 lncRNA probes with p < 1e-03. The top lncRNA probes were annotated to genes, along with the non-coding MALAT1, that play roles in neurodegenerative diseases. The top lncRNAs were linked to functional clusters including peptidyl-glycine modification, vascular smooth muscle cells, mitotic spindle organization and protein tyrosine phosphatase. In addition, mapping of the top significant lncRNAs to the lncRNA-mRNA interaction network detected significantly enriched biological pathways involving neuroactive ligand-receptor interaction, proteasome and chemokines. We show that GCC served as a complementary approach in detecting lncRNAs missed by the conventional linear models. A combination of GCC and linear models identified lncRNAs of diverse patterns of association enriched for GO biological and molecular functions meaningful in cognitive performance and cognitive decline. The novel lncRNA regulatory network further contributed to detect significant pathways implicated in cognition.
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Affiliation(s)
- Afsaneh Mohammadnejad
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark.
| | - Jan Baumbach
- Computational Biomedicine, Department of Mathematics and Computer Science, University of Southern Denmark, Denmark; Chair of Computational Systems Biology, University of Hamburg, Hamburg, Germany.
| | - Weilong Li
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark.
| | - Jesper Lund
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark.
| | - Martin J Larsen
- Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Denmark; Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
| | - Shuxia Li
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark.
| | - Jonas Mengel-From
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Denmark.
| | - Tanja Maria Michel
- Department of Psychiatry, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Psychiatry in the Region of Southern Denmark, Odense University Hospital, Odense, Denmark; Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Lene Christiansen
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - Kaare Christensen
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Denmark.
| | - Jacob Hjelmborg
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark.
| | - Qihua Tan
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Denmark.
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Perluigi M, Di Domenico F, Barone E, Butterfield DA. mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder. Free Radic Biol Med 2021; 169:382-396. [PMID: 33933601 PMCID: PMC8145782 DOI: 10.1016/j.freeradbiomed.2021.04.025] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/15/2021] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.
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Affiliation(s)
- M Perluigi
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - F Di Domenico
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - E Barone
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - D A Butterfield
- Department of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy; Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA.
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Tsakiri EN, Gumeni S, Manola MS, Trougakos IP. Amyloid toxicity in a Drosophila Alzheimer's model is ameliorated by autophagy activation. Neurobiol Aging 2021; 105:137-147. [PMID: 34062489 DOI: 10.1016/j.neurobiolaging.2021.04.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/11/2021] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Alzheimer's disease (AD) is the prevailing form of dementia. Protein degradation and antioxidant pathways have a critical role in preventing the accumulation of protein aggregation; thus, failure of proteostasis in neurons along with redox imbalance mark AD. Herein, we exploited an AD Drosophila model expressing human amyloid precursor (hAPP) and beta-secretase 1 (hBACE1) proteins, to better understand the role of proteostatic or antioxidant pathways in AD. Ubiquitous expression of hAPP, hBACE1 in flies caused more severe degenerative phenotypes versus neuronal targeted expression; it also, suppressed proteasome activity, increased oxidative stress and significantly enhanced stress-sensitivity. Overexpression of Prosβ5 proteasomal subunit or Nrf2 transcription factor in AD Drosophila flies partially restored proteasomal activity but did not rescue hAPP, hBACE1 induced neurodegeneration. On the other hand, expression of autophagy-related Atg8a in AD flies decelerated neurodegeneration, increased stress-resistance, and improved flies' health-/lifespan. Overall, our data suggest that the noxious effects of amyloid-beta aggregates can be alleviated by enhanced autophagy, thus dietary or pharmacological interventions that target autophagy should be considered in AD therapeutic approaches.
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Affiliation(s)
- Eleni N Tsakiri
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece
| | - Sentiljana Gumeni
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece
| | - Maria S Manola
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece
| | - Ioannis P Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
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Chen C, Liu P, Wang J, Yu H, Zhang Z, Liu J, Chen X, Zhu F, Yang X. Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease. Front Cell Dev Biol 2021; 8:624339. [PMID: 33634105 PMCID: PMC7902075 DOI: 10.3389/fcell.2020.624339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/07/2020] [Indexed: 01/04/2023] Open
Abstract
Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. No effective therapy is available for this disease. In this study, we investigated the potential therapeutic effects of dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid, on AD, and found that DAU administration significantly improved cognitive impairments in 3xTg-AD mice by decreasing Aβ plaques and hyperphosphorylated tau and increasing the hippocampal ATP level. Proteomic and western blot analyses revealed that DAU treatment mainly modified the expression of proteins involved in mitochondrial energy metabolism, such as Aco2, Ndufs1, Cox5a, and SDHB, and that of synapse-related proteins such as Syn1 and Syn2. Pathway analysis revealed that DAU modulated the tricarboxylic acid cycle, synaptic vesicle cycle, glycolysis, and gluconeogenesis in 3xTg-AD mice. Our study suggests that DAU may be a potential drug for the treatment of AD.
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Affiliation(s)
- Chongyang Chen
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Pan Liu
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Jing Wang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Haitao Yu
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Zaijun Zhang
- Key Laboratory of Innovative Chemical Drug Research in Cardio-Cerebrovascular Diseases, Institute of New Drug Research and Guangzhou, Jinan University College of Pharmacy, Guangzhou, China
| | - Jianjun Liu
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Xiao Chen
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Feiqi Zhu
- Cognitive Impairment Ward of Neurology Department, The Third Affiliated Hospital of Shenzhen University Medical College, Shenzhen, China
| | - Xifei Yang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
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Piccarducci R, Daniele S, Polini B, Carpi S, Chico L, Fusi J, Baldacci F, Siciliano G, Bonuccelli U, Nieri P, Martini C, Franzoni F. Apolipoprotein E Polymorphism and Oxidative Stress in Human Peripheral Blood Cells: Can Physical Activity Reactivate the Proteasome System through Epigenetic Mechanisms? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8869849. [PMID: 33488947 PMCID: PMC7796851 DOI: 10.1155/2021/8869849] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 11/29/2022]
Abstract
Alzheimer's disease (AD) is characterized by proteasome activity impairment, oxidative stress, and epigenetic changes, resulting in β-amyloid (Aβ) production/degradation imbalance. Apolipoprotein E (ApoE) is implicated in Aβ clearance, and particularly, the ApoE ε4 isoform predisposes to AD development. Regular physical activity is known to reduce AD progression. However, the impact of ApoE polymorphism and physical exercise on Aβ production and proteasome system activity has never been investigated in human peripheral blood cells, particularly in erythrocytes, an emerging peripheral model used to study biochemical alteration. Therefore, the influence of ApoE polymorphism on the antioxidant defences, amyloid accumulation, and proteasome activity was here evaluated in human peripheral blood cells depending on physical activity, to assess putative peripheral biomarkers for AD and candidate targets that could be modulated by lifestyle. Healthy subjects were enrolled and classified based on the ApoE polymorphism (by the restriction fragment length polymorphism technique) and physical activity level (Borg scale) and grouped into ApoE ε4/non-ε4 carriers and active/non-active subjects. The plasma antioxidant capability (AOC), the erythrocyte Aβ production/accumulation, and the nuclear factor erythroid 2-related factor 2 (Nrf2) mediated proteasome functionality were evaluated in all groups by the chromatographic and immunoenzymatic assay, respectively. Moreover, epigenetic mechanisms were investigated considering the expression of histone deacetylase 6, employing a competitive ELISA, and the modulation of two key miRNAs (miR-153-3p and miR-195-5p), through the miRNeasy Serum/Plasma Mini Kit. ApoE ε4 subjects showed a reduction in plasma AOC and an increase in the Nrf2 blocker, miR-153-3p, contributing to an enhancement of the erythrocyte concentration of Aβ. Physical exercise increased plasma AOC and reduced the amount of Aβ and its precursor, involving a reduced miR-153-3p expression and a miR-195-5p enhancement. Our data highlight the impact of the ApoE genotype on the amyloidogenic pathway and the proteasome system, suggesting the positive impact of physical exercise, also through epigenetic mechanisms.
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Affiliation(s)
- Rebecca Piccarducci
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Simona Daniele
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Beatrice Polini
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Sara Carpi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
- NEST, Istituto di Nanoscienze, Consiglio Nazionale delle Ricerche, Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
| | - Lucia Chico
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Jonathan Fusi
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Filippo Baldacci
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Gabriele Siciliano
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Ubaldo Bonuccelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | - Paola Nieri
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Claudia Martini
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
| | - Ferdinando Franzoni
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
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Mladenovic Djordjevic AN, Kapetanou M, Loncarevic-Vasiljkovic N, Todorovic S, Athanasopoulou S, Jovic M, Prvulovic M, Taoufik E, Matsas R, Kanazir S, Gonos ES. Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation. Free Radic Biol Med 2021; 162:88-103. [PMID: 33279620 PMCID: PMC7889698 DOI: 10.1016/j.freeradbiomed.2020.11.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 11/23/2020] [Accepted: 11/28/2020] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.
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Affiliation(s)
- Aleksandra N Mladenovic Djordjevic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia.
| | - Marianna Kapetanou
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635, Athens, Greece
| | - Natasa Loncarevic-Vasiljkovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia; Molecular Nutrition and Health Lab, CEDOC - Centro de Estudos de Doenças Crónicas, NOVA Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Edifício CEDOC II, Rua Câmara Pestana 6, 1150-082, Lisboa, Portugal
| | - Smilja Todorovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia
| | - Sofia Athanasopoulou
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635, Athens, Greece; Department of Biology, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Milena Jovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia
| | - Milica Prvulovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia
| | - Era Taoufik
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521, Athens, Greece
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521, Athens, Greece
| | - Selma Kanazir
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Boulevard Despota Stefana, 142, 11000, Belgrade, Serbia
| | - Efstathios S Gonos
- Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 11635, Athens, Greece.
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Chin TY, Wang CC, Ma KH, Kuo CW, Hu MK, Chueh SH. Antioxidative effect of DJ-1 is enhanced in NG108-15 cells by DPMQ-induced copper influx. Am J Physiol Cell Physiol 2020; 320:C635-C651. [PMID: 33356946 DOI: 10.1152/ajpcell.00515.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Disruption of copper homeostasis is closely involved in neurodegenerative disorders. This study examined whether a hybrid copper-binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), is able to protect NG108-15 cells against oxidative stress. We found that treatment of cells with rotenone or hydrogen peroxide increased cellular oxidative stress and resulted in mitochondrial dysfunction and apoptosis. The cellular levels of Nrf2 and the Cu2+ chaperone DJ-1 were also decreased. These oxidative detrimental effects were all inhibited when cells were cotreated with DPMQ. DPMQ increased cellular Cu2+ content, DJ-1 protein level, superoxide dismutase (SOD) activity, and Nrf2 nuclear translocation under basal state. The activity of SOD decreased under redox imbalance and this decrease was blocked by DPMQ treatment, while the protein level of SOD1 remained unaltered regardless of the oxidative stress and DPMQ treatment. Using endogenous proteins, coimmunoprecipitation showed that DJ-1 bound with SOD1 and Nrf2 individually. The amount of Nrf2, bound to DJ-1, consistently reflected its cellular level, while the amount of SOD1, bound to DJ-1, was potentiated by DPMQ, being greater in the basal state than under redox imbalance. Simultaneous inclusion of nonpermeable Cu2+ chelator tetrathiomolybdate or triethylenetetramine during DPMQ treatment blocked all aforementioned effects of DPMQ, showing that the dependency of the effect of DPMQ on extracellular Cu2+. In addition, silencing of DJ-1 blocked the protection of DPMQ against oxidative stress. Taken all together, our results suggest that DPMQ stabilizes DJ-1 in a Cu2+-dependent manner, which then brings about SOD1 activation and Nrf2 nuclear translocation; these together alleviate cellular oxidative stress.
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Affiliation(s)
- Ting-Yu Chin
- Department of Bioscience Technology, Chung Yuan Christian University, Chungli, Taiwan
| | - Che-Chuan Wang
- Department of Neurosurgery, Chi Mei Medical Center, Tainan, Taiwan.,Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Kuo-Hsing Ma
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Wei Kuo
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Ming-Kuan Hu
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Sheau-Huei Chueh
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
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Pomatto LCD, Sisliyan C, Wong S, Cline M, Tower J, Davies KJA. The proteasome beta 5 subunit is essential for sexually divergent adaptive homeostatic responses to oxidative stress in D. melanogaster. Free Radic Biol Med 2020; 160:67-77. [PMID: 32758664 PMCID: PMC7704559 DOI: 10.1016/j.freeradbiomed.2020.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 11/17/2022]
Abstract
Our studies center on the physiological phenomenon of adaptive homeostasis in which very low, signaling levels of an oxidant can induce transient expansion of the baseline homeostatic range of protective mechanisms, resulting in transient stress protection. The 20S proteasome is a major element of such inducible defense enzymes against oxidative stress but the relative importance of each of its three proteolytic subunits, β1, β2, and β5, is only poorly understood. We focused the present studies on determining the role of the β5 subunit in adaptation, survival, and lifespan. Decreased expression of the 20S proteasome β5 subunit (with RNAi) blocked the adaptive increase in the catalytic activities of the 20S proteasome response to signaling levels of H2O2 in female flies. Similarly, female-specific adaptive increases in survival following H2O2 pretreatment and subsequent toxic challenge was blocked. In contrast, direct overexpression of the 20S proteasome β5 subunit enabled an increased 20S proteasome proteolytic response, but prevented further adaptive homeostatic increases through H2O2 signaling, indicating there is a maximum 'ceiling' to the adaptive response. Males showed no adaptive change in proteasomal levels or activity whatsoever with H2O2 pretreatment and exhibited no significant impact upon the other 2 proteolytic subunits of the proteasome. However, chronic loss of the β5 subunit led to shortened lifespan in both sexes. Our exploration of the importance of the 20S proteasome β5 subunit in adaptive homeostasis highlights the interconnection between signal transduction pathways and regulated gene expression in sexually divergent responses to oxidative stimulation.
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Affiliation(s)
- Laura C D Pomatto
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA; National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Christina Sisliyan
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA
| | - Sarah Wong
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA
| | - Mayme Cline
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA
| | - John Tower
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA; Molecular & Computational Biology Program of the Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, The University of Southern California, Los Angeles, CA, 90089-0191, USA
| | - Kelvin J A Davies
- Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA, 00089-0191, USA; Molecular & Computational Biology Program of the Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, The University of Southern California, Los Angeles, CA, 90089-0191, USA; Department of Biochemistry & Molecular Medicine, Keck School of Medicine of USC, The University of Southern California, Los Angeles, CA, USA.
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Moyano P, Sanjuna J, Garcia JM, Garcia J, Frejo MT, Naval MV, Del Pino J. Paraquat Treatment Compromises the Clearance of β-Amyloid and Tau Proteins and Induces Primary Hippocampal Neuronal Cell Death through HSP70, P20S, and TFEB Disruption. Chem Res Toxicol 2020; 34:1240-1244. [PMID: 33156613 DOI: 10.1021/acs.chemrestox.0c00370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The herbicide paraquat (PQ) induces hippocampal neuronal cell loss and cognitive dysfunction after one and repeated treatment. All the mechanisms involved in these effects are not well understood. Single and repeated PQ treatment increased Aβ and tau protein levels, through HSP70 and TFEB downregulation and proteasome 20S inhibition, producing cell death in primary hippocampal neurons associated with cognitive decline. Our results reveal the mechanisms through which PQ could induce the accumulation of abnormal proteins and neurodegeneration that could originate the cognitive decline produced by it and could help managing its degenerative effects.
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Affiliation(s)
- Paula Moyano
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Javier Sanjuna
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
| | - José Manuel Garcia
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Jimena Garcia
- Department of Pharmacology, Health Sciences School, Alfonso X University, 28691 Madrid, Spain
| | - María Teresa Frejo
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
| | - María Victoria Naval
- Department of Pharmacology, Pharmacognosy and Botany, Pharmacy School, Complutense University of Madrid, 28041 Madrid, Spain
| | - Javier Del Pino
- Department of Pharmacology and Toxicology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain
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Feng T, Yamashita T, Shang J, Shi X, Nakano Y, Morihara R, Tsunoda K, Nomura E, Sasaki R, Tadokoro K, Matsumoto N, Hishikawa N, Ohta Y, Abe K. Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model. J Alzheimers Dis 2020; 71:327-339. [PMID: 31403949 DOI: 10.3233/jad-190369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis.
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Affiliation(s)
- Tian Feng
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Toru Yamashita
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Jingwei Shang
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Xiaowen Shi
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Yumiko Nakano
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Ryuta Morihara
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Keiichiro Tsunoda
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Emi Nomura
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Ryo Sasaki
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Koh Tadokoro
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Namiko Matsumoto
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Nozomi Hishikawa
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Yasuyuki Ohta
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
| | - Koji Abe
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kitaku, Okayama, Japan
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May-Zhang LS, Kirabo A, Huang J, Linton MF, Davies SS, Murray KT. Scavenging Reactive Lipids to Prevent Oxidative Injury. Annu Rev Pharmacol Toxicol 2020; 61:291-308. [PMID: 32997599 DOI: 10.1146/annurev-pharmtox-031620-035348] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Oxidative injury due to elevated levels of reactive oxygen species is implicated in cardiovascular diseases, Alzheimer's disease, lung and liver diseases, and many cancers. Antioxidant therapies have generally been ineffective at treating these diseases, potentially due to ineffective doses but also due to interference with critical host defense and signaling processes. Therefore, alternative strategies to prevent oxidative injury are needed. Elevated levels of reactive oxygen species induce lipid peroxidation, generating reactive lipid dicarbonyls. These lipid oxidation products may be the most salient mediators of oxidative injury, as they cause cellular and organ dysfunction by adducting to proteins, lipids, and DNA. Small-molecule compounds have been developed in the past decade to selectively and effectively scavenge these reactive lipid dicarbonyls. This review outlines evidence supporting the role of lipid dicarbonyls in disease pathogenesis, as well as preclinical data supporting the efficacy of novel dicarbonyl scavengers in treating or preventing disease.
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Affiliation(s)
- Linda S May-Zhang
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
| | - Annet Kirabo
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
| | - Jiansheng Huang
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
| | - MacRae F Linton
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
| | - Sean S Davies
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
| | - Katherine T Murray
- Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA;
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MicroRNAs Dysregulation and Mitochondrial Dysfunction in Neurodegenerative Diseases. Int J Mol Sci 2020; 21:ijms21175986. [PMID: 32825273 PMCID: PMC7504116 DOI: 10.3390/ijms21175986] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/12/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases are debilitating and currently incurable conditions causing severe cognitive and motor impairments, defined by the progressive deterioration of neuronal structure and function, eventually causing neuronal loss. Understand the molecular and cellular mechanisms underlying these disorders are essential to develop therapeutic approaches. MicroRNAs (miRNAs) are short non-coding RNAs implicated in gene expression regulation at the post-transcriptional level. Moreover, miRNAs are crucial for different processes, including cell growth, signal transmission, apoptosis, cancer and aging-related neurodegenerative diseases. Altered miRNAs levels have been associated with the formation of reactive oxygen species (ROS) and mitochondrial dysfunction. Mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. The crosstalk existing among oxidative stress, mitochondrial dysfunction and miRNAs dysregulation plays a pivotal role in the onset and progression of neurodegenerative diseases. Based on this evidence, in this review, with a focus on miRNAs and their role in mitochondrial dysfunction in aging-related neurodegenerative diseases, with a focus on their potential as diagnostic biomarkers and therapeutic targets.
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Michalska P, León R. When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration. Antioxidants (Basel) 2020; 9:antiox9080740. [PMID: 32806679 PMCID: PMC7463521 DOI: 10.3390/antiox9080740] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/27/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022] Open
Abstract
Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.
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Affiliation(s)
- Patrycja Michalska
- Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain
- Correspondence: (P.M.); (R.L.); Tel.: +34-91-497-27-66 (P.M. & R.L.)
| | - Rafael León
- Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain
- Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), 28006 Madrid, Spain
- Correspondence: (P.M.); (R.L.); Tel.: +34-91-497-27-66 (P.M. & R.L.)
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Bagheri F, Rashedi V. Simultaneous exposure to noise and carbon monoxide increases the risk of Alzheimer's disease: a literature review. Med Gas Res 2020; 10:85-90. [PMID: 32541134 PMCID: PMC7885712 DOI: 10.4103/2045-9912.285562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Dementia is a syndrome of cognitive and functional decline, commonly occurring in later life as a result of neurodegenerative and cerebrovascular processes beginning earlier in the life course. An excess of free radicals has an essential role in neurodegenerative diseases and aging. This paper aims to review the effects of noise and carbon monoxide as a risk factor in Alzheimer's disease as well as the role of free radicals in the progress of Alzheimer's disease. Articles included in this review were identified through a search of the databases PubMed, Scopus, and Google Scholar using the search terms Alzheimer's disease, dementia, noise, reactive oxygen species, and Carbon Monoxide. The literature search was restricted to the years 1982 to 2020 and articles published in the English language. The metabolism rate of the body is very high when exposed to noise and carbon monoxide; this leads to overproduction of reactive oxygen species and oxidative stress conditions. Oxidative stress has an essential role in the mechanisms concerned in Alzheimer's disease. In addition to the consequences of noise and a chemical substance on the auditory system, they also have non-auditory effects that affect the brain and induced neurodegenerative disease.
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Affiliation(s)
- Fereshteh Bagheri
- Department of Audiology, School of Rehabilitation Sciences, Babol University of Medical Sciences, Mazandaran, Iran
| | - Vahid Rashedi
- School of Behavioral Sciences and Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, Iran
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Hong G, Zeng P, Li N, Cai H, Guo Y, Li X, Li K, Li H. A Qualitative Analysis Based on Relative Expression Orderings Identifies Transcriptional Subgroups for Alzheimer’s Disease. Curr Alzheimer Res 2020; 16:1175-1182. [PMID: 31763973 DOI: 10.2174/1567205016666191122125035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/10/2019] [Accepted: 11/21/2019] [Indexed: 12/20/2022]
Abstract
Background:
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. However, few studies have investigated the heterogeneous gene expression patterns in AD.
Objective and Methods:
We examined the gene expression patterns in four brain regions of AD based on the within-sample relative expression orderings (REOs). Gene pairs with significantly reversed REOs in AD samples compared to non-AD controls were identified for each brain region using Fisher’s exact test, and filtered according to their transcriptional differences between AD samples. Subgroups of AD were classified by cluster analysis.
Results:
REO-based gene expression profiling analyses revealed that transcriptional differences, as well as distinct disease subsets, existed within AD patients. For each brain region, two main subgroups were classified: one subgroup reported differentially expressed genes overlapped with the age-related genes, and the other might relate to neuroinflammation.
Conclusion:
AD transcriptional subgroups might help understand the underlying pathogenesis of AD, and lend support to a personalized approach to AD management.
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Affiliation(s)
- Guini Hong
- College of Information Engineering, Gannan Medical University, Ganzhou 341000, China
| | - Pengming Zeng
- Department of Bioinformatics, Fujian Medical University, Fuzhou, 350108, China
| | - Na Li
- College of Information Engineering, Gannan Medical University, Ganzhou 341000, China
| | - Hao Cai
- Medical Big Data and Bioinformatics Research Centre at First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - You Guo
- Medical Big Data and Bioinformatics Research Centre at First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Xiaopeng Li
- College of Information Engineering, Gannan Medical University, Ganzhou 341000, China
| | - Keshen Li
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Hongdong Li
- College of Information Engineering, Gannan Medical University, Ganzhou 341000, China
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