|
1
|
Posa A. Spike protein-related proteinopathies: A focus on the neurological side of spikeopathies. Ann Anat 2025; 260:152662. [PMID: 40254264 DOI: 10.1016/j.aanat.2025.152662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND The spike protein (SP) is an outward-projecting transmembrane glycoprotein on viral surfaces. SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), responsible for COVID-19 (Coronavirus Disease 2019), uses SP to infect cells that express angiotensin converting enzyme 2 (ACE2) on their membrane. Remarkably, SP has the ability to cross the blood-brain barrier (BBB) into the brain and cause cerebral damage through various pathomechanisms. To combat the COVID-19 pandemic, novel gene-based products have been used worldwide to induce human body cells to produce SP to stimulate the immune system. This artificial SP also has a harmful effect on the human nervous system. STUDY DESIGN Narrative review. OBJECTIVE This narrative review presents the crucial role of SP in neurological complaints after SARS-CoV-2 infection, but also of SP derived from novel gene-based anti-SARS-CoV-2 products (ASP). METHODS Literature searches using broad terms such as "SARS-CoV-2", "spike protein", "COVID-19", "COVID-19 pandemic", "vaccines", "COVID-19 vaccines", "post-vaccination syndrome", "post-COVID-19 vaccination syndrome" and "proteinopathy" were performed using PubMed. Google Scholar was used to search for topic-specific full-text keywords. CONCLUSIONS The toxic properties of SP presented in this review provide a good explanation for many of the neurological symptoms following SARS-CoV-2 infection and after injection of SP-producing ASP. Both SP entities (from infection and injection) interfere, among others, with ACE2 and act on different cells, tissues and organs. Both SPs are able to cross the BBB and can trigger acute and chronic neurological complaints. Such SP-associated pathologies (spikeopathies) are further neurological proteinopathies with thrombogenic, neurotoxic, neuroinflammatory and neurodegenerative potential for the human nervous system, particularly the central nervous system. The potential neurotoxicity of SP from ASP needs to be critically examined, as ASPs have been administered to millions of people worldwide.
Collapse
Affiliation(s)
- Andreas Posa
- University Clinics and Outpatient Clinics for Radiology, Neuroradiology and Neurology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, Halle 06120, Germany.
| |
Collapse
|
|
2
|
Sălcudean A, Bodo CR, Popovici RA, Cozma MM, Păcurar M, Crăciun RE, Crisan AI, Enatescu VR, Marinescu I, Cimpian DM, Nan AG, Sasu AB, Anculia RC, Strete EG. Neuroinflammation-A Crucial Factor in the Pathophysiology of Depression-A Comprehensive Review. Biomolecules 2025; 15:502. [PMID: 40305200 PMCID: PMC12024626 DOI: 10.3390/biom15040502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Depression is a multifactorial psychiatric condition with complex pathophysiology, increasingly linked to neuroinflammatory processes. The present review explores the role of neuroinflammation in depression, focusing on glial cell activation, cytokine signaling, blood-brain barrier dysfunction, and disruptions in neurotransmitter systems. The article highlights how inflammatory mediators influence brain regions implicated in mood regulation, such as the hippocampus, amygdala, and prefrontal cortex. The review further discusses the involvement of the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the kynurenine pathway, providing mechanistic insights into how chronic inflammation may underlie emotional and cognitive symptoms of depression. The bidirectional relationship between inflammation and depressive symptoms is emphasized, along with the role of peripheral immune responses and systemic stress. By integrating molecular, cellular, and neuroendocrine perspectives, this review supports the growing field of immunopsychiatry and lays the foundation for novel diagnostic biomarkers and anti-inflammatory treatment approaches in depression. Further research in this field holds promise for developing more effective and personalized interventions for individuals suffering from depression.
Collapse
Affiliation(s)
- Andreea Sălcudean
- Department of Ethics and Social Sciences, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania; (A.S.); (M.-M.C.); (D.-M.C.)
| | - Cristina-Raluca Bodo
- Department of Ethics and Social Sciences, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania; (A.S.); (M.-M.C.); (D.-M.C.)
| | - Ramona-Amina Popovici
- Department of Management and Communication in Dental Medicine, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy of Timisoara, 9 Revolutiei 1989 Bv., 300070 Timisoara, Romania
| | - Maria-Melania Cozma
- Department of Ethics and Social Sciences, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania; (A.S.); (M.-M.C.); (D.-M.C.)
| | - Mariana Păcurar
- Orthodontic Department, Faculty of Dental Medicine, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mures, Romania;
| | | | - Andrada-Ioana Crisan
- Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania;
| | - Virgil-Radu Enatescu
- Department of Psychiatry, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania;
| | - Ileana Marinescu
- Discipline of Psychiatry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Dora-Mihaela Cimpian
- Department of Ethics and Social Sciences, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania; (A.S.); (M.-M.C.); (D.-M.C.)
| | - Andreea-Georgiana Nan
- First Department of Psychiatry, Clinical County Hospital of Targu Mures, 540142 Târgu Mureș, Romania; (A.-G.N.); (A.-B.S.)
| | - Andreea-Bianca Sasu
- First Department of Psychiatry, Clinical County Hospital of Targu Mures, 540142 Târgu Mureș, Romania; (A.-G.N.); (A.-B.S.)
| | - Ramona-Camelia Anculia
- Discipline of Occupational Medicine, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy of Timisoara, 300041 Timișoara, Romania;
| | - Elena-Gabriela Strete
- Department of Psychiatry, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Târgu Mureș, Romania;
| |
Collapse
|
|
3
|
Wertman E. Essential New Complexity-Based Themes for Patient-Centered Diagnosis and Treatment of Dementia and Predementia in Older People: Multimorbidity and Multilevel Phenomenology. J Clin Med 2024; 13:4202. [PMID: 39064242 PMCID: PMC11277671 DOI: 10.3390/jcm13144202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/12/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Dementia is a highly prevalent condition with devastating clinical and socioeconomic sequela. It is expected to triple in prevalence by 2050. No treatment is currently known to be effective. Symptomatic late-onset dementia and predementia (SLODP) affects 95% of patients with the syndrome. In contrast to trials of pharmacological prevention, no treatment is suggested to remediate or cure these symptomatic patients. SLODP but not young onset dementia is intensely associated with multimorbidity (MUM), including brain-perturbating conditions (BPCs). Recent studies showed that MUM/BPCs have a major role in the pathogenesis of SLODP. Fortunately, most MUM/BPCs are medically treatable, and thus, their treatment may modify and improve SLODP, relieving suffering and reducing its clinical and socioeconomic threats. Regrettably, the complex system features of SLODP impede the diagnosis and treatment of the potentially remediable conditions (PRCs) associated with them, mainly due to failure of pattern recognition and a flawed diagnostic workup. We suggest incorporating two SLODP-specific conceptual themes into the diagnostic workup: MUM/BPC and multilevel phenomenological themes. By doing so, we were able to improve the diagnostic accuracy of SLODP components and optimize detecting and favorably treating PRCs. These revolutionary concepts and their implications for remediability and other parameters are discussed in the paper.
Collapse
Affiliation(s)
- Eli Wertman
- Department of Neurology, Hadassah University Hospital, The Hebrew University, Jerusalem 9190500, Israel;
- Section of Neuropsychology, Department of Psychology, The Hebrew University, Jerusalem 9190500, Israel
- Or’ad: Organization for Cognitive and Behavioral Changes in the Elderly, Jerusalem 9458118, Israel
- Merhav Neuropsychogeriatric Clinics, Nehalim 4995000, Israel
| |
Collapse
|
|
4
|
Paret H, Vahia IV. Is Alzheimer's disease a single illness or multiple illnesses? Int Psychogeriatr 2024; 36:161-162. [PMID: 36594252 DOI: 10.1017/s1041610222001065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Hayley Paret
- Division of Geriatric Psychiatry, McLean Hospital, Belmont, MA, USA
| | - Ipsit V Vahia
- Division of Geriatric Psychiatry, McLean Hospital, Belmont, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
5
|
Duchesne S, Rousseau LS, Belzile-Marsolais F, Welch LA, Cournoyer B, Arseneau M, Lapierre V, Poulin SM, Potvin O, Hudon C. A Scoping Review of Alzheimers Disease Hypotheses: An Array of Uni- and Multi-Factorial Theories. J Alzheimers Dis 2024; 99:843-856. [PMID: 38788067 PMCID: PMC11191496 DOI: 10.3233/jad-230772] [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] [Accepted: 03/27/2024] [Indexed: 05/26/2024]
Abstract
Background There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Objective To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. Results We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. Results Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. Conclusions When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.
Collapse
Affiliation(s)
- Simon Duchesne
- Department of Radiology and Nuclear Medicine, Université, Laval, Quebec City, QC, Canada
| | - Louis-Simon Rousseau
- CERVO Brain Research Centre, Quebec City, QC, Canada
- School of Psychology, Université, Laval, Quebec City, QC, Canada
| | - Florence Belzile-Marsolais
- CERVO Brain Research Centre, Quebec City, QC, Canada
- School of Psychology, Université, Laval, Quebec City, QC, Canada
| | - Laurie-Ann Welch
- CERVO Brain Research Centre, Quebec City, QC, Canada
- School of Psychology, Université, Laval, Quebec City, QC, Canada
| | | | | | - Véronick Lapierre
- CERVO Brain Research Centre, Quebec City, QC, Canada
- School of Psychology, Université, Laval, Quebec City, QC, Canada
| | | | - Olivier Potvin
- Quebec Heart and Lung Research Institute, Quebec City, QC, Canada
- CERVO Brain Research Centre, Quebec City, QC, Canada
| | - Carol Hudon
- CERVO Brain Research Centre, Quebec City, QC, Canada
- School of Psychology, Université, Laval, Quebec City, QC, Canada
- VITAM Research Centre, Quebec City, QC, Canada
| |
Collapse
|
|
6
|
Andrade-Guerrero J, Santiago-Balmaseda A, Jeronimo-Aguilar P, Vargas-Rodríguez I, Cadena-Suárez AR, Sánchez-Garibay C, Pozo-Molina G, Méndez-Catalá CF, Cardenas-Aguayo MDC, Diaz-Cintra S, Pacheco-Herrero M, Luna-Muñoz J, Soto-Rojas LO. Alzheimer's Disease: An Updated Overview of Its Genetics. Int J Mol Sci 2023; 24:ijms24043754. [PMID: 36835161 PMCID: PMC9966419 DOI: 10.3390/ijms24043754] [Citation(s) in RCA: 137] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/16/2023] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1-5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.
Collapse
Affiliation(s)
- Jesús Andrade-Guerrero
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, Querétaro, Mexico
| | - Alberto Santiago-Balmaseda
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
| | - Paola Jeronimo-Aguilar
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico
| | - Isaac Vargas-Rodríguez
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, Querétaro, Mexico
| | - Ana Ruth Cadena-Suárez
- National Dementia BioBank, Ciencias Biológicas, Facultad de Estudios Superiores Cuautitlán, Universidad-Nacional Autónoma de México, Cuatitlan 53150, Edomex, Mexico
| | - Carlos Sánchez-Garibay
- Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México 14269, Mexico
| | - Glustein Pozo-Molina
- Laboratorio de Genética y Oncología Molecular, Laboratorio 5, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
| | - Claudia Fabiola Méndez-Catalá
- Laboratorio de Genética y Oncología Molecular, Laboratorio 5, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- División de Investigación y Posgrado, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Edomex, Mexico
| | - Maria-del-Carmen Cardenas-Aguayo
- Laboratory of Cellular Reprogramming, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Sofía Diaz-Cintra
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla 76230, Querétaro, Mexico
| | - Mar Pacheco-Herrero
- Neuroscience Research Laboratory, Faculty of Health Sciences, Pontificia Universidad Católica Madre y Maestra, Santiago de los Caballeros 51000, Dominican Republic
| | - José Luna-Muñoz
- National Dementia BioBank, Ciencias Biológicas, Facultad de Estudios Superiores Cuautitlán, Universidad-Nacional Autónoma de México, Cuatitlan 53150, Edomex, Mexico
- National Brain Bank-UNPHU, Universidad Nacional Pedro Henríquez Ureña, Santo Domingo 1423, Dominican Republic
- Correspondence: (J.L.-M.); (L.O.S.-R.); Tel.: +52-55-45-23-41-20 (J.L.-M.); +52-55-39-37-94-30 (L.O.S.-R.)
| | - Luis O. Soto-Rojas
- Laboratorio de Patogénesis Molecular, Laboratorio 4, Edificio A4, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Red MEDICI, Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Edomex, Mexico
- Correspondence: (J.L.-M.); (L.O.S.-R.); Tel.: +52-55-45-23-41-20 (J.L.-M.); +52-55-39-37-94-30 (L.O.S.-R.)
| |
Collapse
|
|
7
|
What increases the risk of gamers being addicted? An integrated network model of personality–emotion–motivation of gaming disorder. COMPUTERS IN HUMAN BEHAVIOR 2022. [DOI: 10.1016/j.chb.2022.107647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
8
|
Cao Y, Zhang R. The application of nanotechnology in treatment of Alzheimer's disease. Front Bioeng Biotechnol 2022; 10:1042986. [PMID: 36466349 PMCID: PMC9713307 DOI: 10.3389/fbioe.2022.1042986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/02/2022] [Indexed: 09/19/2023] Open
Abstract
The buildup of beta-amyloid plaques in the brain results in Alzheimer's disease (AD), a neurodegenerative condition. A permanent treatment for AD is not yet available. Only a slowing down of its advancement is possible with the current pharmaceutical options. Nevertheless, nanotechnology has proven to be advantageous in medical applications. It has a lot of potential for AD therapy, particularly in diagnosing the condition and providing an alternative course of treatment. In this review, we outline the developments and benefits of nanomedicines in treating AD. Prospective nanomedicines for diagnosing and surveillance therapeutic interventions for AD and other diseases of the central nervous system (CNS) may be clinically accessible, persuading the development of investigation in this field.
Collapse
Affiliation(s)
- Yanyan Cao
- Department of Neurology, First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | | |
Collapse
|
|
9
|
Wu JP. Combined Ketogenic Diet and Walking Exercise Interventions in Community Older Frailty and Skeletal Muscle Sarcopenia. FRAILTY AND SARCOPENIA - RECENT EVIDENCE AND NEW PERSPECTIVES 2022. [DOI: 10.5772/intechopen.101579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2025]
Abstract
The ketogenic diet and walking exercise training interventions are two key public health lifestyle factors. The potential of combined lifestyle factors interventions focused on getting to compliance in diet and exercise. A balanced ketogenic diet and regular exercise interventions is key modifiable factor to the prevention and management of community older frailty and skeletal muscle sarcopenia. Influence health across the lifespan and reduction of the risk of premature death through several biochemistry mechanisms. Community older group’s lifestyle factors interventions contribute identity in their natural living environment. While the older health benefits of walking exercise training interventions strategies are commonly to study, combining ketogenic diet and walking exercise interventions can induce greater benefits in community older groups.
Collapse
|
|
10
|
Trebesova H, Olivero G, Marchi M, Grilli M. The Anti-Aggregative Peptide KLVFF Mimics Aβ1-40 in the Modulation of Nicotinic Receptors: Implications for Peptide-Based Therapy. Biomedicines 2022; 10:biomedicines10092231. [PMID: 36140331 PMCID: PMC9496455 DOI: 10.3390/biomedicines10092231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/31/2022] [Accepted: 09/05/2022] [Indexed: 12/02/2022] Open
Abstract
In recent years, the inhibition of beta-amyloid (Aβ) aggregation has emerged as a potential strategy for Alzheimer’s disease. KLVFF, a small peptide corresponding to the aminoacidic sequence 16-20 of Aβ, reduces Aβ fibrillation dose dependently. Therefore, the toxic and functional characterization of its brain activity is fundamental for clarifying its potential therapeutic role. Accordingly, we studied the modulatory role of KLVFF on the cholinergic receptors regulating dopamine and noradrenaline release in rat synaptosomes. Nicotinic receptors on dopaminergic nerve terminals in the nucleus acccumbens are inhibited by KLVFF, which closely resembles full-length Aβ1-40. Moreover, KLVFF entrapped in synaptosomes does not modify the nicotinic receptor’s function, suggesting that external binding to the receptor is required for its activity. The cholinergic agent desformylflustrabromine counteracts the KLVFF effect. Remarkably, muscarinic receptors on dopaminergic terminals and nicotinic receptors regulating noradrenaline release in the hippocampus are completely insensitive to KLVFF. Based on our findings, KLVFF mimics Aβ1-40 as a negative modulator of specific nicotinic receptor subtypes affecting dopamine transmission in the rat brain. Therefore, new pharmacological strategies using the anti-aggregative properties of KLVFF need to be evaluated for potential interference with nicotinic receptor-mediated transmission.
Collapse
|
|
11
|
Perry BL, McConnell WR, Coleman ME, Roth AR, Peng S, Apostolova LG. Why the cognitive "fountain of youth" may be upstream: Pathways to dementia risk and resilience through social connectedness. Alzheimers Dement 2022; 18:934-941. [PMID: 34482619 PMCID: PMC8897512 DOI: 10.1002/alz.12443] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/07/2021] [Accepted: 07/07/2021] [Indexed: 12/21/2022]
Abstract
Research suggests social connectedness may help older adults with dementia maintain cognitive functionality and quality of life. However, little is known about its specific social and biological mechanisms. This paper proposes two pathways through social bridging (i.e., cognitive enrichment through expansive social networks) and bonding (i.e., neuroendocrine benefits of integration in cohesive social networks). We provide preliminary evidence for these pathways using neuroimaging, cognitive, and egocentric social network data from the Social Networks and Alzheimer's Disease (SNAD) study (N = 280). We found that network size, density, and presence of weak ties (i.e., social bridging) moderated the association between brain atrophy and cognitive function, while marriage/cohabitation (i.e., social bonding) moderated the association between perceived stress and cognitive function. We argue that social connectedness may have downstream implications for multiple pathophysiological processes in cognitive aging, even negating existing structural damage to the brain, making it a strong candidate for clinical or policy intervention.
Collapse
Affiliation(s)
- Brea L Perry
- Department of Sociology, Indiana University, Bloomington, Indiana, USA
| | - Will R McConnell
- Department of Sociology, Florida Atlantic University, Boca Raton, Florida, USA
| | - Max E Coleman
- Department of Sociology, Indiana University, Bloomington, Indiana, USA
| | - Adam R Roth
- Department of Sociology, Indiana University, Bloomington, Indiana, USA
| | - Siyun Peng
- Department of Sociology, Indiana University, Bloomington, Indiana, USA
| | - Liana G Apostolova
- Departments of Neurology, Radiology and Medical and Molecular Genetics, Indiana University School of Medicine, IU Health Neuroscience Center, Indianapolis, Indiana, USA
| |
Collapse
|
|
12
|
Jana A, Bhattacharjee A, Das SS, Srivastava A, Choudhury A, Bhattacharjee R, De S, Perveen A, Iqbal D, Gupta PK, Jha SK, Ojha S, Singh SK, Ruokolainen J, Jha NK, Kesari KK, Ashraf GM. Molecular Insights into Therapeutic Potentials of Hybrid Compounds Targeting Alzheimer's Disease. Mol Neurobiol 2022; 59:3512-3528. [PMID: 35347587 PMCID: PMC9148293 DOI: 10.1007/s12035-022-02779-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/21/2022] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is one of the most complex progressive neurological disorders involving degeneration of neuronal connections in brain cells leading to cell death. AD is predominantly detected among elder people (> 65 years), mostly diagnosed with the symptoms of memory loss and cognitive dysfunctions. The multifarious pathogenesis of AD comprises the accumulation of pathogenic proteins, decreased neurotransmission, oxidative stress, and neuroinflammation. The conventional therapeutic approaches are limited to symptomatic benefits and are ineffective against disease progression. In recent years, researchers have shown immense interest in the designing and fabrication of various novel therapeutics comprised of naturally isolated hybrid molecules. Hybrid therapeutic compounds are developed from the combination of pharmacophores isolated from bioactive moieties which specifically target and block various AD-associated pathogenic pathways. The method of designing hybrid molecules has numerous advantages over conventional multitarget drug development methods. In comparison to in silico high throughput screening, hybrid molecules generate quicker results and are also less expensive than fragment-based drug development. Designing hybrid-multitargeted therapeutic compounds is thus a prospective approach in developing an effective treatment for AD. Nevertheless, several issues must be addressed, and additional researches should be conducted to develop hybrid therapeutic compounds for clinical usage while keeping other off-target adverse effects in mind. In this review, we have summarized the recent progress on synthesis of hybrid compounds, their molecular mechanism, and therapeutic potential in AD. Using synoptic tables, figures, and schemes, the review presents therapeutic promise and potential for the development of many disease-modifying hybrids into next-generation medicines for AD.
Collapse
Affiliation(s)
- Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed To Be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Arkadyuti Bhattacharjee
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed To Be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Sabya Sachi Das
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Avani Srivastava
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed To Be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Akshpita Choudhury
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed To Be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Rahul Bhattacharjee
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed To Be University, Campus-11, Patia, Bhubaneswar, Odisha, 751024, India
| | - Swagata De
- Department of English, DDE Unit, The University of Burdwan, GolapbagBurdwan, West Bengal, 713104, India
| | - Asma Perveen
- Glocal School of Life Sciences, Glocal University, Mirzapur Pole, Saharanpur, Uttar Pradesh, India
| | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah, 11952, Saudi Arabia
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research (SBSR), Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, 15551, Al Ain, United Arab Emirates
| | - Sandeep Kumar Singh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Janne Ruokolainen
- Department of Applied Physics, School of Science, Aalto University, 00076, Espoo, Finland
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India.
| | - Kavindra Kumar Kesari
- Department of Applied Physics, School of Science, Aalto University, 00076, Espoo, Finland.
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. .,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| |
Collapse
|
|
13
|
Santos G, Díaz M. Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer's Disease. Predictions from an Agent-Based Mathematical Model. Int J Mol Sci 2021; 22:ijms222212181. [PMID: 34830060 PMCID: PMC8620379 DOI: 10.3390/ijms222212181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/02/2021] [Accepted: 11/07/2021] [Indexed: 11/30/2022] Open
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.
Collapse
Affiliation(s)
- Guido Santos
- Systems Biology and Mathematical Modelling Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Biology Section, Science School, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
- Correspondence:
| | - Mario Díaz
- Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Science School, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain;
- IUETSP (Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias), Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| |
Collapse
|
|
14
|
Zhu Y, Han X, Li X, Qin Y, Rang Y, Zhai X, Lu Y. Quantitation of six steroid hormones by ultra-performance liquid chromatography-tandem mass spectrometry in plasma and prefrontal cortex samples from rats with chronic unpredictable mild stress-induced depression. Biomed Chromatogr 2021; 35:e5200. [PMID: 34128243 DOI: 10.1002/bmc.5200] [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: 10/28/2020] [Revised: 06/06/2021] [Accepted: 06/10/2021] [Indexed: 11/10/2022]
Abstract
Steroid hormones such as glucocorticoids and their metabolites are closely related to mental diseases and neuroendocrine diseases. Quantitative analysis of these substances will help in understanding their roles in related research fields. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to detect the concentration of corticosterone (CORT) and its metabolites, progesterone (PROG) and testosterone in rat plasma and prefrontal cortex (PFC), and was applied to investigate the changes in hormones in rats with depression induced by chronic unpredictable mild stress (CUMS). The method was shown to be linear in the quantitation range for all analytes. Intra- and inter-day accuracy and precision were between 80% and 120%. Furthermore, we found that the level of CORT in plasma and PFC increased, whereas that of 11-dehydrocorticosterone (11-DHCORT) as well as the ratio of 11-DHCORT and CORT declined in rats with CUMS-induced depression. The trends of these changes in central PFC and peripheral plasma were consistent. In conclusion, this study successfully established an UPLC-MS/MS method for simultaneous measurement of CORT and its metabolites, PROG and testosterone in rat plasma and PFC, and applied it to rats with depression. The method could be further applied to the research of depression and diseases related to these steroid hormones.
Collapse
Affiliation(s)
- Ying Zhu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuemei Han
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, Hubei, China
| | - Xixuan Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanjie Qin
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, Hubei, China
| | - Ying Rang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, Hubei, China
| | - Xuejia Zhai
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, Hubei, China
| | - Yongning Lu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, Hubei, China
| |
Collapse
|
|
15
|
Khan NH, Mir M, Ngowi EE, Zafar U, Khakwani MMAK, Khattak S, Zhai YK, Jiang ES, Zheng M, Duan SF, Wei JS, Wu DD, Ji XY. Nanomedicine: A Promising Way to Manage Alzheimer's Disease. Front Bioeng Biotechnol 2021; 9:630055. [PMID: 33996777 PMCID: PMC8120897 DOI: 10.3389/fbioe.2021.630055] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/08/2021] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease (AD) is a devastating disease of the aging population characterized by the progressive and slow brain decay due to the formation of extracellular plaques in the hippocampus. AD cells encompass tangles of twisted strands of aggregated microtubule binding proteins surrounded by plaques. Delivering corresponding drugs in the brain to deal with these clinical pathologies, we face a naturally built strong, protective barrier between circulating blood and brain cells called the blood-brain barrier (BBB). Nanomedicines provide state-of-the-art alternative approaches to overcome the challenges in drug transport across the BBB. The current review presents the advances in the roles of nanomedicines in both the diagnosis and treatment of AD. We intend to provide an overview of how nanotechnology has revolutionized the approaches used to manage AD and highlight the current key bottlenecks and future perspective in this field. Furthermore, the emerging nanomedicines for managing brain diseases like AD could promote the booming growth of research and their clinical availability.
Collapse
Affiliation(s)
- Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Maria Mir
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ebenezeri Erasto Ngowi
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Department of Biological Sciences, Faculty of Sciences, Dar es Salaam University College of Education, Dar es Salaam, Tanzania
| | - Ujala Zafar
- School of Natural Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | | | - Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yuan-Kun Zhai
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- School of Stomatology, Henan University, Kaifeng, China
| | - En-She Jiang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Institutes of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, China
| | - Meng Zheng
- International Joint Center for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, China
| | - Shao-Feng Duan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Jian-She Wei
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Brain Research Laboratory, School of Life Sciences, Henan University, Kaifeng, China
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- School of Stomatology, Henan University, Kaifeng, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical Sciences, Henan University, Kaifeng, China
| |
Collapse
|
|
16
|
Leblhuber F, Ehrlich D, Steiner K, Geisler S, Fuchs D, Lanser L, Kurz K. The Immunopathogenesis of Alzheimer's Disease Is Related to the Composition of Gut Microbiota. Nutrients 2021; 13:361. [PMID: 33504065 PMCID: PMC7912578 DOI: 10.3390/nu13020361] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 12/11/2022] Open
Abstract
The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.
Collapse
Affiliation(s)
- Friedrich Leblhuber
- Department of Gerontology, Neuromed Campus, Kepler University Clinic, Linz A-4020, Austria; (F.L.); (D.E.); (K.S.)
| | - Daniela Ehrlich
- Department of Gerontology, Neuromed Campus, Kepler University Clinic, Linz A-4020, Austria; (F.L.); (D.E.); (K.S.)
| | - Kostja Steiner
- Department of Gerontology, Neuromed Campus, Kepler University Clinic, Linz A-4020, Austria; (F.L.); (D.E.); (K.S.)
| | - Simon Geisler
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck A-6020, Austria; (S.G.); (D.F.)
| | - Dietmar Fuchs
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck A-6020, Austria; (S.G.); (D.F.)
| | - Lukas Lanser
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck A-6020, Austria;
| | - Katharina Kurz
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck A-6020, Austria;
| |
Collapse
|
|
17
|
Dogra A, Narang RS, Narang JK. Recent Advances in Nanotherapeutic Interventions for the Treatment of Alzheimer's Disease. Curr Pharm Des 2020; 26:2257-2279. [PMID: 32321393 DOI: 10.2174/1381612826666200422092620] [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] [Received: 11/16/2019] [Accepted: 03/06/2020] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD), with impairment of learning and memory as the common clinical manifestations, is one of the most challenging diseases affecting individuals, their families and society as a whole. The fact that its prevalence is escalating rapidly, with the total number of AD patients estimated to reach 115.4 million by 2050, has made the disease a very challenging ailment worldwide. Several biological barriers like the bloodbrain barrier (BBB), drug efflux by P-glycoprotein and the blood-cerebrospinal fluid barrier restrict the delivery of conventional AD drugs to the central nervous system (CNS), thereby limiting their effectiveness. In order to overcome the above physiological barriers, the development of nanomedicines has been extensively explored. The present review provides an insight into the pathophysiology of AD and risk factors associated with AD. Besides, various nanoformulations reported in the literature for the diagnosis and treatments of AD have been classified and summarised. The patented nanoformulations for AD and details of nanoformulations which are in clinical trials are also mentioned. The review would be helpful to researchers and scientific community by providing them with information related to the recent advances in nanointerventions for the diagnosis and treatment of AD, which they can further explore for better management of the disease. However, although the nanotherapeutics for managing AD have been extensively explored, the factors which hinder their commercialisation, the toxicity concern being one of them, need to be addressed so that effective nanotherapeutics for AD can be developed for clinical use.
Collapse
Affiliation(s)
- Anmol Dogra
- Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India.,I.K. Gujral Punjab Technical University, Kapurthala, Punjab, India
| | - R S Narang
- Department of Oral & Maxillofacial Pathology and Microbiology, Sri Guru Ram Das Institute of Dental Sciences and Research, Amritsar, Punjab, India
| | - Jasjeet K Narang
- Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
| |
Collapse
|
|
18
|
Fessel J. Ineffective levels of transforming growth factors and their receptor account for old age being a risk factor for Alzheimer's disease. ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS 2019; 5:899-905. [PMID: 31890854 PMCID: PMC6926356 DOI: 10.1016/j.trci.2019.11.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
After the midninth decade of age, the incidence rates of Alzheimer's disease (AD) and the presence of active TGF-β1 show comparable increases. The hypothesis is proposed that the reason why advanced age is a major risk factor for AD is a progressive decrease with advancing age in the numbers of TGFR2 receptors in the brain, with the consequence of a decline in the neurotrophic efficacy of TGF-β1 and 2 despite their already increased levels in older persons. Alternative, possible reasons are discussed but rejected because either those reasons may also affect young persons or because they cannot be validated in a clinical trial. The proposed hypothesis may be validated in persons with aMCI after raising their brain levels of TGF-β1 and 2 by using a combination of three drugs, lithium, memantine, plus either glatiramer or venlafaxine, and then assessing their progression to AD.
Collapse
Affiliation(s)
- Jeffrey Fessel
- Emeritus, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
19
|
Harilal S, Jose J, Parambi DGT, Kumar R, Mathew GE, Uddin MS, Kim H, Mathew B. Advancements in nanotherapeutics for Alzheimer’s disease: current perspectives. J Pharm Pharmacol 2019; 71:1370-1383. [DOI: 10.1111/jphp.13132] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 06/15/2019] [Indexed: 02/06/2023]
Abstract
Abstract
Objectives
Considerable progress has been made in the treatment of Alzheimer’s disease (AD), but all available strategies focus on alleviating symptoms rather than curing, which means that AD is viewed as an unresolvable neurodegenerative disease. Nanotechnological applications offer an alternative platform for the treatment of neurodegenerative diseases. This review aims to summarize the recent nanomedicine and nanotechnology developments for the treatment of AD.
Key findings
A plethora of nanocarriers and nanoparticle prodrugs have been reported to have negligible cytotoxicity in animal models, and these developments have revealed new opportunities for development of new classes of potent drug formulations for AD. Different nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes and metal-based carriers have been developed over the past decade, and they have been focusing on both neuroprotective and neurogenerative techniques to treat AD. Studies also reveal that nanotechnological approaches can aid in early diagnosis of AD and enhance therapeutic efficacy and bioavailability.
Summary
Notably, the drugs used conventionally to target the central nervous system have limitations that include an inability to cross the ‘blood–brain barrier’ or the ‘blood–cerebrospinal fluid barrier’ effectively and high drug efflux due to the activity of P-glycoprotein, but these limitations can be successfully overcome when nanocarriers are used for targeted drug delivery in AD.
Collapse
Affiliation(s)
- Seetha Harilal
- Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Jobin Jose
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Science, NITTE Deemed to be University, Mangalore, India
| | | | - Rajesh Kumar
- Kerala University of Health Sciences, Thrissur, Kerala, India
| | | | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Hoon Kim
- Department of Pharmacy, Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, Korea
| | - Bijo Mathew
- Division of Drug Design, Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala, India
| |
Collapse
|
|
20
|
Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern RA. Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment. J Alzheimers Dis 2019; 62:1841-1855. [PMID: 29614641 DOI: 10.3233/jad-170527] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. OBJECTIVE The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. METHOD The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). RESULTS 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. DISCUSSION The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.
Collapse
Affiliation(s)
- Michael A Sugarman
- Boston University Alzheimer's Disease Center, Boston, MA, USA.,Department of Psychology, Bedford Veterans Affairs Medical Center, Boston, MA, USA
| | - Michael L Alosco
- Boston University Alzheimer's Disease Center, Boston, MA, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| | - Yorghos Tripodis
- Boston University Alzheimer's Disease Center, Boston, MA, USA.,Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | | | - Robert A Stern
- Boston University Alzheimer's Disease Center, Boston, MA, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, USA.,Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA.,Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA
| |
Collapse
|
|
21
|
Abstract
The history of neuroscience is the memory of the discipline and this memory depends on the study of the present traces of the past; the things left behind: artifacts, equipment, written documents, data books, photographs, memoirs, etc. History, in all of its definitions, is an integral part of neuroscience and I have used examples from the literature and my personal experience to illustrate the importance of the different aspects of history in neuroscience. Each time we talk about the brain, do an experiment, or write a research article, we are involved in history. Each published experiment becomes a historical document; it relies on past research (the "Introduction" section), procedures developed in the past ("Methods" section) and as soon as new data are published, they become history and become embedded into the history of the discipline ("Discussion" section). In order to be transparent and able to be replicated, each experiment requires its own historical archive. Studying history means researching books, documents and objects in libraries, archives, and museums. It means looking at data books, letters and memos, talking to scientists, and reading biographies and autobiographies. History can be made relevant by integrating historical documents into classes and by using historical websites. Finally, conducting historical research can be interesting, entertaining, and can lead to travel to out-of-the-way and exotic places and meeting interesting people.
Collapse
Affiliation(s)
- Richard E. Brown
- Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada
| |
Collapse
|
|
22
|
The internal link of serum steroid hormones levels in insomnia, depression, and Alzheimer's disease rats: Is there an effective way to distinguish among these three diseases based on potential biomarkers? J Sep Sci 2019; 42:1833-1841. [DOI: 10.1002/jssc.201801298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/20/2019] [Accepted: 03/02/2019] [Indexed: 11/07/2022]
|
|
23
|
Drobyshev EJ, Solovyev ND, Gorokhovskiy BM, Kashuro VA. Accumulation Patterns of Sub-chronic Aluminum Toxicity Model After Gastrointestinal Administration in Rats. Biol Trace Elem Res 2018; 185:384-394. [PMID: 29441448 DOI: 10.1007/s12011-018-1247-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/11/2018] [Indexed: 01/08/2023]
Abstract
Although aluminum chronic neurotoxicity is well documented, there are no well-established experimental protocols of Al exposure. In the current study, toxic effects of sub-chronic Al exposure have been evaluated in outbreed male rats (gastrointestinal administration). Forty animals were used: 10 were administered with AlCl3 water solution (2 mg/kg Al per day) for 1 month, 10 received the same concentration of AlCl3 for 3 month, and 20 (10 per observation period) saline as control. After 30 and 90 days, the animals underwent behavioral tests: open field, passive avoidance, extrapolation escape task, and grip strength. At the end of the study, the blood, liver, kidney, and brain were excised for analytical and morphological studies. The Al content was measured by inductively coupled plasma mass-spectrometry. Essential trace elements-Co, Cr, Cu, Fe, Mg, Mn, Mo, Se, and Zn-were measured in whole blood samples. Although no morphological changes were observed in the brain, liver, or kidney for both exposure terms, dose-dependent Al accumulation and behavioral differences (increased locomotor activity after 30 days) between treatment and control groups were indicated. Moreover, for 30 days exposure, strong positive correlation between Al content in the brain and blood for individual animals was established, which surprisingly disappeared by the third month. This may indicate neural barrier adaptation to the Al exposure or the saturation of Al transport into the brain. Notably, we could not see a clear neurodegeneration process after rather prolonged sub-chronic Al exposure, so probably longer exposure periods are required.
Collapse
Affiliation(s)
- Evgenii J Drobyshev
- Institut für Ernährungswissenschaft, Universität Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal, 14558, Potsdam, Germany.
- St. Petersburg State University, St. Petersburg, Russia.
| | | | - Boris M Gorokhovskiy
- Institute of Precambrian Geology and Geochronology Russian Academy of Sciences, St. Petersburg, Russia
| | - Vadim A Kashuro
- Institute of Toxicology of Federal Medico-Biological Agency, St. Petersburg, Russia
| |
Collapse
|
|
24
|
Roterman I, Banach M, Konieczny L. Towards the design of anti-amyloid short peptide helices. Bioinformation 2018; 14:1-7. [PMID: 29497253 PMCID: PMC5818643 DOI: 10.6026/97320630014001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 01/25/2018] [Accepted: 01/25/2018] [Indexed: 12/11/2022] Open
Abstract
A set of short peptide sequences susceptible to fibrillar aggregation produces sequneces capable of arresting elongation of amyloid fibrils. The "stop" signals are short helices customized for each individual target. Such a helix should exhibit high amphiphilicity, with differing conditions present on each side (one side should be highly hydrophilic to enable water to interact with the aggregate, while the other side must retain a local distribution of hydrophobicity which matches that of the terminal portion of the fibril). The emergence and elongation of fibrillary forms resulting from linear propagation of local hydrophobicity peaks is shown using the fuzzy oil drop model.
Collapse
Affiliation(s)
- Irena Roterman
- Department of Bioinformatics and Telemedicine, Jagiellonian University-Medical College, Lazarza 16, 31-530 Krakow, Poland
| | - Mateusz Banach
- Department of Bioinformatics and Telemedicine, Jagiellonian University-Medical College, Lazarza 16, 31-530 Krakow, Poland
| | - Leszek Konieczny
- Chair of Medical Biochemistry, Jagiellonian University-Medical College, Kopernika 7, 31-034 Krakow, Poland
| |
Collapse
|
|
25
|
D'Cunha NM, McKune AJ, Panagiotakos DB, Georgousopoulou EN, Thomas J, Mellor DD, Naumovski N. Evaluation of dietary and lifestyle changes as modifiers of S100β levels in Alzheimer's disease. Nutr Neurosci 2017; 22:1-18. [PMID: 28696163 DOI: 10.1080/1028415x.2017.1349032] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There is a significant body of research undertaken in order to elucidate the mechanisms underlying the pathology of Alzheimer's disease (AD), as well as to discover early detection biomarkers and potential therapeutic strategies. One such proposed biomarker is the calcium binding protein S100β, which, depending on its local concentration, is known to exhibit both neurotrophic and neuroinflammatory properties in the central nervous system. At present, relatively little is known regarding the effect of chronic S100β disruption in AD. Dietary intake has been identified as a modifiable risk factor for AD. Preliminary in vitro and animal studies have demonstrated an association between S100β expression and dietary intake which links to AD pathophysiology. This review describes the association of S100β to fatty acids, ketone bodies, insulin, and botanicals as well as the potential impact of physical activity as a lifestyle factor. We also discuss the prospective implications of these findings, including support of the use of a Mediterranean dietary pattern and/or the ketogenic diet as an approach to modify AD risk.
Collapse
Affiliation(s)
- Nathan M D'Cunha
- a University of Canberra Health Research Institute (UCHRI) , University of Canberra , Locked Bag 1, Bruce , Canberra ACT 2601 , Australia.,b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia
| | - Andrew J McKune
- b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia.,c University of Canberra, Research Institute for Sport and Exercise , University of Canberra , Bruce , Canberra ACT 2601 , Australia.,d Discipline of Biokinetics, Exercise and Leisure Sciences, School of Health Sciences , University of KwaZulu-Natal , Durban 4041 , South Africa
| | - Demosthenes B Panagiotakos
- e Department of Nutrition-Dietetics, School of Health and Education , Harokopio University , Athens 176 71 , Greece
| | - Ekavi N Georgousopoulou
- b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia.,e Department of Nutrition-Dietetics, School of Health and Education , Harokopio University , Athens 176 71 , Greece
| | - Jackson Thomas
- a University of Canberra Health Research Institute (UCHRI) , University of Canberra , Locked Bag 1, Bruce , Canberra ACT 2601 , Australia.,b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia
| | - Duane D Mellor
- a University of Canberra Health Research Institute (UCHRI) , University of Canberra , Locked Bag 1, Bruce , Canberra ACT 2601 , Australia.,b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia
| | - Nenad Naumovski
- a University of Canberra Health Research Institute (UCHRI) , University of Canberra , Locked Bag 1, Bruce , Canberra ACT 2601 , Australia.,b Collaborative Research in Bioactives and Biomarkers Group (CRIBB) , University of Canberra , Bruce , Canberra ACT 2601 , Australia
| |
Collapse
|
|
26
|
Fu L, Li Y, Hu Y, Zheng Y, Yu B, Zhang H, Wu J, Wu H, Yu X, Kong W. Norovirus P particle-based active Aβ immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease. Sci Rep 2017; 7:41041. [PMID: 28106117 PMCID: PMC5247735 DOI: 10.1038/srep41041] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 12/15/2016] [Indexed: 12/14/2022] Open
Abstract
Disease-modifying immunotherapies focusing on reducing amyloid-beta (Aβ) deposition are the main treatment for Alzheimer’s disease (AD). However, none of the Aβ immunotherapies has produced clinically meaningful results to date. The main reason for this lack of efficacy is that the vaccine induces insufficiently high antibody titers, as it contains small B-cell epitope of Aβ to avoid Aβ42-specific T-cell activation. With the aim of generating a potent AD vaccine, we designed the protein PP-3copy-Aβ1-6-loop123, comprising three copies of Aβ1-6 inserted into three loops of a novel vaccine platform, the norovirus P particle, which could present Aβ at its surface and remarkably enhance the immunogenicity of the vaccine. We demonstrated that PP-3copy-Aβ1-6-loop123 was able to elicit high antibody titers against Aβ42, without causing T-cell activation, in AD mice regardless of their age. Importantly, PP-3copy-Aβ1-6-loop123 treatment successfully reduced amyloid deposition, rescued memory loss, and repaired hippocampus damage in AD mice. The Aβ antibodies induced by this active immunotherapy reacted with and disrupted aggregated Aβ, reducing its cellular toxicity. In addition, our results suggested PP-3copy-Aβ1-6-loop123 immunization could restore Aβ42 homeostasis in both the serum and brain. Thus, the P particle-based Aβ epitope vaccine is a sufficiently immunogenic and safe immunotherapeutic intervention for Alzheimer’s disease.
Collapse
Affiliation(s)
- Lu Fu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yingnan Li
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yue Hu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yayuan Zheng
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Bin Yu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Haihong Zhang
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Jiaxin Wu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Hui Wu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Xianghui Yu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Wei Kong
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.,Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| |
Collapse
|
|
27
|
Functional modulation of strychnine-sensitive glycine receptors in rat hippocampal pyramidal neurons by amyloid-β protein (1-42). Brain Res 2016; 1651:61-72. [DOI: 10.1016/j.brainres.2016.09.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/07/2016] [Accepted: 09/09/2016] [Indexed: 11/17/2022]
|