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Stephens MC, Li J, Mair M, Moore J, Zhu K, Tarkunde A, Amoh B, Perez AM, Bhakare A, Guo F, Shulman JM, Al-Ramahi I, Botas J. Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease. Am J Hum Genet 2025; 112:1081-1096. [PMID: 40215969 PMCID: PMC12120185 DOI: 10.1016/j.ajhg.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 05/04/2025] Open
Abstract
Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available orthologs in two well-established Drosophila AD models that express either wild-type tau or secreted β-amyloid (β42). Experimental perturbation of the 60 available candidates pinpointed 46 that modulated neuronal dysfunction in one or both fly models. The effects of 18 of these genes were concordant with the TWAS prediction, such that the direction of misexpression predicted to increase AD risk in humans exacerbated behavioral impairments in the AD fly models. Reversing the aberrant down- or upregulation of 11 of these genes (MTCH2, ELL, TAP2, HDC, DMWD, MYCL, SLC4A9, ABCA7, CSTF1, PTK2B, and CD2AP) proved neuroprotective in vivo. We further studied MTCH2 and found that it regulates steady-state tau protein levels in the Drosophila brain and reduces tau accumulation in human neural progenitor cells. This systematic, integrative approach effectively prioritizes genes at GWAS loci and reveals promising AD-relevant candidates for further investigation as risk factors or targets for therapeutic intervention.
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Affiliation(s)
- Morgan C Stephens
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Jiayang Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Megan Mair
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Justin Moore
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Katy Zhu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Akash Tarkunde
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Bismark Amoh
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Alma M Perez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Arya Bhakare
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Fangfei Guo
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA
| | - Joshua M Shulman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ismael Al-Ramahi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA
| | - Juan Botas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA.
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Wang NQ, Sun PX, Shen QQ, Deng MY. Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets. Mol Neurobiol 2025; 62:6283-6307. [PMID: 39775479 DOI: 10.1007/s12035-024-04672-w] [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: 09/19/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025]
Abstract
The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.
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Affiliation(s)
- Ning-Qi Wang
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450001, China
| | - Pei-Xiang Sun
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450001, China
| | - Qi-Qi Shen
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450001, China
| | - Meng-Yan Deng
- Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Perks CM, Barker RM, Alhadrami M, Alkahtani O, Gill E, Grishaw M, Harland AJ, Henley P, Li H, O’Sullivan E, Stone G, Su X, Kehoe PG. Curious Dichotomies of Apolipoprotein E Function in Alzheimer's Disease and Cancer-One Explanatory Mechanism of Inverse Disease Associations? Genes (Basel) 2025; 16:331. [PMID: 40149482 PMCID: PMC11942319 DOI: 10.3390/genes16030331] [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: 02/17/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
An apparent "inverse" relationship exists between two seemingly unconnected conditions, Alzheimer's disease (AD) and cancer, despite sharing similar risk factors, like increased age and obesity. AD is associated with amyloid beta (Aβ) plaques and neurofibrillary tau tangles that cause neural degeneration; cancer, in contrast, is characterized by enhanced cell survival and proliferation. Apolipoprotein E (ApoE) is the main lipoprotein found in the central nervous system and via its high affinity with lipoprotein receptors plays a critical role in cholesterol transport and uptake. ApoE has 3 protein isoforms, ApoE E2, ApoE E3, and ApoE E4, respectively encoded for by 3 allelic variants of APOE (ε2, ε3, and ε4). This review examines the characteristics and function of ApoE described in both AD and cancer to assimilate evidence for its potential contribution to mechanisms that may underly the reported inverse association between the two conditions. Of the genetic risk factors relevant to most cases of AD, the most well-known with the strongest contribution to risk is APOE, specifically the ε4 variant, whereas for cancer risk, APOE has not featured as a significant genetic contributor to risk. However, at the protein level in both conditions, ApoE contributes to disease pathology via affecting lipid physiology and transport. In AD, Aβ-dependent and -independent interactions have been suggested, whereas in cancer, ApoE plays a role in immunoregulation. Understanding the mechanism of action of ApoE in these diametrically opposed diseases may enable differential targeting of therapeutics to provide a beneficial outcome for both.
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Affiliation(s)
- Claire M. Perks
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Rachel M. Barker
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Mai Alhadrami
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Omar Alkahtani
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Emily Gill
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Mary Grishaw
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Abigail J. Harland
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Peter Henley
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Haonan Li
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Ellie O’Sullivan
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Gideon Stone
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Xiaoyu Su
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Patrick G. Kehoe
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
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Christ W, Kapell S, Sobkowiak MJ, Mermelekas G, Evertsson B, Sork H, Saher O, Bazaz S, Gustafsson O, Cardenas EI, Villa V, Ricciarelli R, Sandberg JK, Bergquist J, Sturchio A, Svenningsson P, Malm T, Espay AJ, Pernemalm M, Lindén A, Klingström J, El Andaloussi S, Ezzat K. SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion. ACS Chem Neurosci 2024; 15:4095-4104. [PMID: 39510798 DOI: 10.1021/acschemneuro.4c00636] [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: 11/15/2024] Open
Abstract
The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogeneous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as APLP1 (amyloid β precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin, and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.
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Affiliation(s)
- Wanda Christ
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Sebastian Kapell
- Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1 Chome-12-4 Sakamoto, Nagasaki 852-8102, Japan
| | - Michal J Sobkowiak
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Georgios Mermelekas
- Cancer Proteomics Mass Spectrometry, SciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Björn Evertsson
- Department of Clinical Neuroscience and Centrum for Molecular Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Helena Sork
- Institute of Technology, University of Tartu, 50411 Tartu, Estonia
| | - Osama Saher
- Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt
| | - Safa Bazaz
- Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Oskar Gustafsson
- Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Eduardo I Cardenas
- Division of Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Viviana Villa
- Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy
| | - Roberta Ricciarelli
- Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Johan K Sandberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Jonas Bergquist
- Department of Chemistry-Biomedical Center, Analytical Chemistry and Neuro Chemistry, Uppsala University, 75105 Uppsala, Sweden
| | - Andrea Sturchio
- Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, 17177 Stockholm, Sweden
- James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio 45267-0525, United States
| | - Per Svenningsson
- Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Tarja Malm
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
| | - Alberto J Espay
- James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio 45267-0525, United States
| | - Maria Pernemalm
- Cancer Proteomics Mass Spectrometry, SciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Anders Lindén
- Division of Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
- Karolinska Severe COPD Center, Department of Respiratory Medicine and Allergy, Karolinska University Hospital, 17177 Stockholm, Sweden
| | - Jonas Klingström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Samir El Andaloussi
- Biomolecular and Cellular Medicine (BCM), Department of Laboratory Medicine, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Kariem Ezzat
- Regain Therapeutics, Novum, 14157 Stockholm, Sweden
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Takasugi M, Nonaka Y, Takemura K, Yoshida Y, Stein F, Schwarz JJ, Adachi J, Satoh J, Ito S, Tombline G, Biashad SA, Seluanov A, Gorbunova V, Ohtani N. An atlas of the aging mouse proteome reveals the features of age-related post-transcriptional dysregulation. Nat Commun 2024; 15:8520. [PMID: 39353907 PMCID: PMC11445428 DOI: 10.1038/s41467-024-52845-x] [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: 07/03/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
To what extent and how post-transcriptional dysregulation affects aging proteome remains unclear. Here, we provide proteomic data of whole-tissue lysates (WTL) and low-solubility protein-enriched fractions (LSF) of major tissues collected from mice of 6, 15, 24, and 30 months of age. Low-solubility proteins are preferentially affected by age and the analysis of LSF doubles the number of proteins identified to be differentially expressed with age. Simultaneous analysis of proteome and transcriptome using the same tissue homogenates reveals the features of age-related post-transcriptional dysregulation. Post-transcriptional dysregulation becomes evident especially after 24 months of age and age-related post-transcriptional dysregulation leads to accumulation of core matrisome proteins and reduction of mitochondrial membrane proteins in multiple tissues. Based on our in-depth proteomic data and sample-matched transcriptome data of adult, middle-aged, old, and geriatric mice, we construct the Mouse aging proteomic atlas ( https://aging-proteomics.info/ ), which provides a thorough and integrative view of age-related gene expression changes.
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Affiliation(s)
- Masaki Takasugi
- Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan.
| | - Yoshiki Nonaka
- Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
| | - Kazuaki Takemura
- Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
| | - Yuya Yoshida
- Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
| | - Frank Stein
- Proteomic Core Facility, EMBL Heidelberg, Heidelberg, Germany
| | | | - Jun Adachi
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Junko Satoh
- Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Ito
- Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Gregory Tombline
- Department of Biology, University of Rochester, Rochester, NY, USA
| | | | - Andrei Seluanov
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Vera Gorbunova
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Naoko Ohtani
- Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan.
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Rueter J, Rimbach G, Bilke S, Tholey A, Huebbe P. Readdressing the Localization of Apolipoprotein E (APOE) in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes (MAMs): An Investigation of the Hepatic Protein-Protein Interactions of APOE with the Mitochondrial Proteins Lon Protease (LONP1), Mitochondrial Import Receptor Subunit TOM40 (TOMM40) and Voltage-Dependent Anion-Selective Channel 1 (VDAC1). Int J Mol Sci 2024; 25:10597. [PMID: 39408926 PMCID: PMC11476584 DOI: 10.3390/ijms251910597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
As a component of circulating lipoproteins, APOE binds to cell surface receptors mediating lipoprotein metabolism and cholesterol transport. A growing body of evidence, including the identification of a broad variety of cellular proteins interacting with APOE, suggests additional independent functions. Investigating cellular localization and protein-protein interactions in cultured human hepatocytes, we aimed to contribute to the elucidation of hitherto unnoted cellular functions of APOE. We observed a strong accumulation of APOE in MAMs, equally evident for the two major isoforms APOE3 and APOE4. Using mass spectrometry proteome analyses, novel and previously noted APOE interactors were identified, including the mitochondrial proteins TOMM40, LONP1 and VDAC1. All three interactors were present in MAM fractions, which we think initially facilitates interactions with APOE. LONP1 is a protease with chaperone activity, which migrated to MAMs in response to ER stress, displaying a reinforced interaction with APOE. We therefore hypothesize that APOE may help in the unfolded protein response (UPR) by acting as a co-chaperone in cooperation with LONP1 at the interface of mitochondria and ER membranes. The interaction of APOE with the integral proteins TOMM40 and VDAC1 may point to the formation of bridging complexes connecting mitochondria with other organelles.
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Affiliation(s)
- Johanna Rueter
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
| | - Stephanie Bilke
- Institute of Experimental Medicine, University of Kiel, Niemannsweg 11, 24105 Kiel, Germany
| | - Andreas Tholey
- Institute of Experimental Medicine, University of Kiel, Niemannsweg 11, 24105 Kiel, Germany
| | - Patricia Huebbe
- Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany; (J.R.); (G.R.)
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Moon HJ, Luo Y, Chugh D, Zhao L. Human apolipoprotein E glycosylation and sialylation: from structure to function. Front Mol Neurosci 2024; 17:1399965. [PMID: 39169951 PMCID: PMC11335735 DOI: 10.3389/fnmol.2024.1399965] [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: 03/12/2024] [Accepted: 06/28/2024] [Indexed: 08/23/2024] Open
Abstract
Human apolipoprotein E (ApoE) was first identified as a polymorphic gene in the 1970s; however, the genetic association of ApoE genotypes with late-onset sporadic Alzheimer's disease (sAD) was only discovered 20 years later. Since then, intensive research has been undertaken to understand the molecular effects of ApoE in the development of sAD. Despite three decades' worth of effort and over 10,000 papers published, the greatest mystery in the ApoE field remains: human ApoE isoforms differ by only one or two amino acid residues; what is responsible for their significantly distinct roles in the etiology of sAD, with ApoE4 conferring the greatest genetic risk for sAD whereas ApoE2 providing exceptional neuroprotection against sAD. Emerging research starts to point to a novel and compelling hypothesis that the sialoglycans posttranslationally appended to human ApoE may serve as a critical structural modifier that alters the biology of ApoE, leading to the opposing impacts of ApoE isoforms on sAD and likely in the peripheral systems as well. ApoE has been shown to be posttranslationally glycosylated in a species-, tissue-, and cell-specific manner. Human ApoE, particularly in brain tissue and cerebrospinal fluid (CSF), is highly glycosylated, and the glycan chains are exclusively attached via an O-linkage to serine or threonine residues. Moreover, studies have indicated that human ApoE glycans undergo sialic acid modification or sialylation, a structural alteration found to be more prominent in ApoE derived from the brain and CSF than plasma. However, whether the sialylation modification of human ApoE has a biological role is largely unexplored. Our group recently first reported that the three major isoforms of human ApoE in the brain undergo varying degrees of sialylation, with ApoE2 exhibiting the most abundant sialic acid modification, whereas ApoE4 is the least sialylated. Our findings further indicate that the sialic acid moiety on human ApoE glycans may serve as a critical modulator of the interaction of ApoE with amyloid β (Aβ) and downstream Aβ pathogenesis, a prominent pathologic feature in AD. In this review, we seek to provide a comprehensive summary of this exciting and rapidly evolving area of ApoE research, including the current state of knowledge and opportunities for future exploration.
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Affiliation(s)
- Hee-Jung Moon
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States
| | - Yan Luo
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States
| | - Diksha Chugh
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States
| | - Liqin Zhao
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States
- Neuroscience Graduate Program, University of Kansas, Lawrence, KS, United States
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8
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Jackson RJ, Hyman BT, Serrano-Pozo A. Multifaceted roles of APOE in Alzheimer disease. Nat Rev Neurol 2024; 20:457-474. [PMID: 38906999 DOI: 10.1038/s41582-024-00988-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2024] [Indexed: 06/23/2024]
Abstract
For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-β - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.
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Affiliation(s)
- Rosemary J Jackson
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Bradley T Hyman
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Massachusetts Alzheimer's Disease Research Center, Charlestown, MA, USA.
| | - Alberto Serrano-Pozo
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Massachusetts Alzheimer's Disease Research Center, Charlestown, MA, USA.
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9
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Grenon MB, Papavergi MT, Bathini P, Sadowski M, Lemere CA. Temporal Characterization of the Amyloidogenic APPswe/PS1dE9;hAPOE4 Mouse Model of Alzheimer's Disease. Int J Mol Sci 2024; 25:5754. [PMID: 38891941 PMCID: PMC11172317 DOI: 10.3390/ijms25115754] [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: 05/04/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
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Affiliation(s)
- Martine B. Grenon
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.B.G.); (M.-T.P.); (P.B.)
- Section Neuropsychology & Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Maria-Tzousi Papavergi
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.B.G.); (M.-T.P.); (P.B.)
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Praveen Bathini
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.B.G.); (M.-T.P.); (P.B.)
| | - Martin Sadowski
- Departments of Neurology, Psychiatry, and Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA;
| | - Cynthia A. Lemere
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.B.G.); (M.-T.P.); (P.B.)
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10
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Thierry M, Ponce J, Martà-Ariza M, Askenazi M, Faustin A, Leitner D, Pires G, Kanshin E, Drummond E, Ueberheide B, Wisniewski T. The influence of APOE ε4 on the pTau interactome in sporadic Alzheimer's disease. Acta Neuropathol 2024; 147:91. [PMID: 38772917 PMCID: PMC11108952 DOI: 10.1007/s00401-024-02744-8] [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: 03/11/2024] [Revised: 04/12/2024] [Accepted: 05/12/2024] [Indexed: 05/23/2024]
Abstract
APOEε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOEε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (fold change ≥ 1.50, IPPHF1 vs IPIgG ctrl). We identified 80 and 68 proteins as probable pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOEε3/ε3 vs APOEε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOEε4/ε4 vs APOEε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOEε4 carriers, paving the way to the identification of new therapeutic targets.
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Affiliation(s)
- Manon Thierry
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA.
| | - Jackeline Ponce
- Department of Biochemistry and Molecular Pharmacology, Proteomics Laboratory, Grossman School of Medicine, New York University, New York, NY, USA
| | - Mitchell Martà-Ariza
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Arline Faustin
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA
| | - Dominique Leitner
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA
- Department of Neurology, Comprehensive Epilepsy Center, Grossman School of Medicine, New York University, New York, NY, USA
| | - Geoffrey Pires
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA
| | - Evgeny Kanshin
- Department of Biochemistry and Molecular Pharmacology, Proteomics Laboratory, Grossman School of Medicine, New York University, New York, NY, USA
| | - Eleanor Drummond
- Brain and Mind Centre, School of Medical Science, University of Sydney, Sydney, Australia
| | - Beatrix Ueberheide
- Department of Biochemistry and Molecular Pharmacology, Proteomics Laboratory, Grossman School of Medicine, New York University, New York, NY, USA
| | - Thomas Wisniewski
- Department of Neurology, Center for Cognitive Neurology, Grossman School of Medicine, New York University, Science Building, Rm 1023J, 435 East 30th Street, New York, NY, USA.
- Departments of Pathology and Psychiatry, Grossman School of Medicine, New York University, Science Building, Rm 1017, 435 East 30 Street, New York, NY, 10016, USA.
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11
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Merle DA, Sen M, Armento A, Stanton CM, Thee EF, Meester-Smoor MA, Kaiser M, Clark SJ, Klaver CCW, Keane PA, Wright AF, Ehrmann M, Ueffing M. 10q26 - The enigma in age-related macular degeneration. Prog Retin Eye Res 2023; 96:101154. [PMID: 36513584 DOI: 10.1016/j.preteyeres.2022.101154] [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: 09/14/2022] [Revised: 11/21/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022]
Abstract
Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.
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Affiliation(s)
- David A Merle
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department of Ophthalmology, Medical University of Graz, 8036, Graz, Austria.
| | - Merve Sen
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany
| | - Angela Armento
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany
| | - Chloe M Stanton
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Eric F Thee
- Department of Ophthalmology, Erasmus University Medical Center, 3015GD, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015CE, Rotterdam, Netherlands
| | - Magda A Meester-Smoor
- Department of Ophthalmology, Erasmus University Medical Center, 3015GD, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015CE, Rotterdam, Netherlands
| | - Markus Kaiser
- Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, 45117, Essen, Germany
| | - Simon J Clark
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Caroline C W Klaver
- Department of Ophthalmology, Erasmus University Medical Center, 3015GD, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015CE, Rotterdam, Netherlands; Department of Ophthalmology, Radboudumc, 6525EX, Nijmegen, Netherlands; Institute of Molecular and Clinical Ophthalmology Basel, CH-4031, Basel, Switzerland
| | - Pearse A Keane
- Institute for Health Research, Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, London, EC1V 2PD, UK
| | - Alan F Wright
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Michael Ehrmann
- Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, 45117, Essen, Germany
| | - Marius Ueffing
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany.
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12
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Sawmiller D, Koyama N, Fujiwara M, Segawa T, Maeda M, Mori T. Targeting apolipoprotein E and N-terminal amyloid β-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice. J Biol Chem 2023; 299:104846. [PMID: 37211092 PMCID: PMC10331488 DOI: 10.1016/j.jbc.2023.104846] [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: 08/09/2022] [Revised: 05/09/2023] [Accepted: 05/13/2023] [Indexed: 05/23/2023] Open
Abstract
Apolipoprotein E (apoE) interaction with amyloid β-protein precursor (APP) has garnered attention as the therapeutic target for Alzheimer's disease (AD). Having discovered the apoE antagonist (6KApoEp) that blocks apoE binding to N-terminal APP, we tested the therapeutic potential of 6KApoEp on AD-relevant phenotypes in amyloid β-protein precursor/presenilin 1 (APP/PS1) mice that express each human apoE isoform of apoE2, apoE3, or apoE4 (designated APP/PS1/E2, APP/PS1/E3, or APP/PS1/E4 mice). At 12 months of age, we intraperitoneally administered 6KApoEp (250 μg/kg) or vehicle once daily for 3 months. At 15 months of age, blockage of apoE and N-terminal APP interaction by 6KApoEp treatment improved cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse line and did not alter behavior in nontransgenic littermates. Moreover, 6KApoEp therapy ameliorated brain parenchymal and cerebral vascular β-amyloid deposits and decreased abundance of amyloid β-protein (Aβ) in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse group. Notably, the highest effect in Aβ-lowering by 6KApoEp treatment was observed in APP/PS1/E4 mice versus APP/PS1/E2 or APP/PS1/E3 mice. These effects occured through shifting toward lessened amyloidogenic APP processing due to decreasing APP abundance at the plasma membrane, reducing APP transcription, and inhibiting p44/42 mitogen-activated protein kinase phosphorylation. Our findings provide the preclinical evidence that 6KApoEp therapy aimed at targeting apoE and N-terminal APP interaction is a promising strategy and may be suitable for patients with AD carrying the apoE4 isoform.
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Affiliation(s)
- Darrell Sawmiller
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
| | - Naoki Koyama
- Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan
| | - Masakazu Fujiwara
- Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan
| | - Tatsuya Segawa
- Immuno-Biological Laboratories Co, Ltd, Fujioka, Gunma, Japan
| | - Masahiro Maeda
- Immuno-Biological Laboratories Co, Ltd, Fujioka, Gunma, Japan
| | - Takashi Mori
- Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan; Department of Pathology, Saitama Medical Center and University, Kawagoe, Saitama, Japan.
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13
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Qiu W, Liu H, Liu Y, Lu X, Wang L, Hu Y, Feng F, Li Q, Sun H. Regulation of beta-amyloid for the treatment of Alzheimer's disease: Research progress of therapeutic strategies and bioactive compounds. Med Res Rev 2023. [PMID: 36945751 DOI: 10.1002/med.21947] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/09/2023] [Accepted: 02/26/2023] [Indexed: 03/23/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is difficult to treat. Extracellular amyloid is the principal pathological criterion for the diagnosis of AD. Amyloid β (Aβ) interacts with various receptor molecules on the plasma membrane and mediates a series of signaling pathways that play a vital role in the occurrence and development of AD. Research on receptors that interact with Aβ is currently ongoing. Overall, there are no effective medications to treat AD. In this review, we first discuss the importance of Aβ in the pathogenesis of AD, then summarize the latest progress of Aβ-related targets and compounds. Finally, we put forward the challenges and opportunities in the development of effective AD therapies.
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Affiliation(s)
- Weimin Qiu
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hui Liu
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yijun Liu
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xin Lu
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanyu Hu
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Feng Feng
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
- Department of Natural Medicinal Chemistry, Jiangsu Food and Pharmaceuticals Science College, Institute of Food and Pharmaceuticals Research, Jiangsu, Huaian, China
| | - Qi Li
- Department of Pharmacology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Haopeng Sun
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
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14
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Absmeier RM, Rottenaicher GJ, Svilenov HL, Kazman P, Buchner J. Antibodies gone bad - the molecular mechanism of light chain amyloidosis. FEBS J 2023; 290:1398-1419. [PMID: 35122394 DOI: 10.1111/febs.16390] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/19/2022] [Accepted: 02/03/2022] [Indexed: 12/19/2022]
Abstract
Light chain amyloidosis (AL) is a systemic disease in which abnormally proliferating plasma cells secrete large amounts of mutated antibody light chains (LCs) that eventually form fibrils. The fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. The prognosis for patients diagnosed with AL is generally poor. The disease is set apart from other amyloidoses by the huge number of patient-specific mutations in the disease-causing and fibril-forming protein. The molecular mechanisms that drive the aggregation of mutated LCs into fibrils have been enigmatic, which hindered the development of efficient diagnostics and therapies. In this review, we summarize our current knowledge on AL amyloidosis and discuss open issues.
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Affiliation(s)
- Ramona M Absmeier
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Georg J Rottenaicher
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Hristo L Svilenov
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Pamina Kazman
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Johannes Buchner
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
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15
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Braun JEA. Extracellular chaperone networks and the export of J-domain proteins. J Biol Chem 2023; 299:102840. [PMID: 36581212 PMCID: PMC9867986 DOI: 10.1016/j.jbc.2022.102840] [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: 09/19/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022] Open
Abstract
An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular milieu face numerous challenges that can lead to protein misfolding and aggregation. As a checkpoint for proteins that move between cells, extracellular chaperone networks are of growing clinical relevance. J-domain proteins (JDPs) are ubiquitous molecular chaperones that are known for their essential roles in a wide array of fundamental cellular processes through their regulation of heat shock protein 70s. As the largest molecular chaperone family, JDPs have long been recognized for their diverse functions within cells. Some JDPs are elegantly selective for their "client proteins," some do not discriminate among substrates and others act cooperatively on the same target. The realization that JDPs are exported through both classical and unconventional secretory pathways has fueled investigation into the roles that JDPs play in protein quality control and intercellular communication. The proposed functions of exported JDPs are diverse. Studies suggest that export of DnaJB11 enhances extracellular proteostasis, that intercellular movement of DnaJB1 or DnaJB6 enhances the proteostasis capacity in recipient cells, whereas the import of DnaJB8 increases resistance to chemotherapy in recipient cancer cells. In addition, the export of DnaJC5 and concurrent DnaJC5-dependent ejection of dysfunctional and aggregation-prone proteins are implicated in the prevention of neurodegeneration. This review provides a brief overview of the current understanding of the extracellular chaperone networks and outlines the first wave of studies describing the cellular export of JDPs.
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Affiliation(s)
- Janice E A Braun
- Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
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16
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Fernandez A, Gomez MT, Vidal R. Lack of ApoE inhibits ADan amyloidosis in a mouse model of familial Danish dementia. J Biol Chem 2022; 299:102751. [PMID: 36436561 PMCID: PMC9792896 DOI: 10.1016/j.jbc.2022.102751] [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: 09/02/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/26/2022] Open
Abstract
The Apolipoprotein E-ε4 allele (APOE-ε4) is the strongest genetic risk factor for late onset Alzheimer disease (AD). ApoE plays a critical role in amyloid-β (Aβ) accumulation in AD, and genetic deletion of the murine ApoE gene in mouse models results in a decrease or inhibition of Aβ deposition. The association between the presence of ApoE and amyloid in amyloidoses suggests a more general role for ApoE in the fibrillogenesis process. However, whether decreasing levels of ApoE would attenuate amyloid pathology in different amyloidoses has not been directly addressed. Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease characterized by the presence of widespread parenchymal and vascular Danish amyloid (ADan) deposition and neurofibrillary tangles. A transgenic mouse model for FDD (Tg-FDD) is characterized by parenchymal and vascular ADan deposition. To determine the effect of decreasing ApoE levels on ADan accumulation in vivo, we generated a mouse model by crossing Tg-FDD mice with ApoE KO mice (Tg-FDD+/-/ApoE-/-). Lack of ApoE results in inhibition of ADan deposition up to 18 months of age. Additionally, our results from a genetic screen of Tg-FDD+/-/ApoE-/- mice emphasize the significant role for ApoE in neurodegeneration in FDD via glial-mediated mechanisms. Taken together, our findings suggest that the interaction between ApoE and ADan plays a key role in FDD pathogenesis, in addition to the known role for ApoE in amyloid plaque formation in AD.
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Affiliation(s)
- Anllely Fernandez
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Maria-Teresa Gomez
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ruben Vidal
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA,Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA,For correspondence: Ruben Vidal
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17
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Dincer A, Chen CD, McKay NS, Koenig LN, McCullough A, Flores S, Keefe SJ, Schultz SA, Feldman RL, Joseph-Mathurin N, Hornbeck RC, Cruchaga C, Schindler SE, Holtzman DM, Morris JC, Fagan AM, Benzinger TLS, Gordon BA. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Sci Transl Med 2022; 14:eabl7646. [PMID: 36383681 PMCID: PMC9912474 DOI: 10.1126/scitranslmed.abl7646] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.
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Affiliation(s)
- Aylin Dincer
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Charles D Chen
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Nicole S McKay
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Lauren N Koenig
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Austin McCullough
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Shaney Flores
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Sarah J Keefe
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Stephanie A Schultz
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Rebecca L Feldman
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Nelly Joseph-Mathurin
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Russ C Hornbeck
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Carlos Cruchaga
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
| | - Suzanne E Schindler
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
| | - David M Holtzman
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.,Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA
| | - John C Morris
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Anne M Fagan
- Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Tammie LS Benzinger
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA
| | - Brian A Gordon
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.,Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.,Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA.,Department of Psychological & Brain Sciences, Washington University, Saint Louis, MO, USA
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18
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Pinals RL, Tsai LH. Building in vitro models of the brain to understand the role of APOE in Alzheimer's disease. Life Sci Alliance 2022; 5:5/11/e202201542. [PMID: 36167428 PMCID: PMC9515460 DOI: 10.26508/lsa.202201542] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022] Open
Abstract
Alzheimer's disease (AD) is a devastating, complex, and incurable disease that represents an increasingly problematic global health issue. The etiology of sporadic AD that accounts for a vast majority of cases remains poorly understood, with no effective therapeutic interventions. Genetic studies have identified AD risk genes including the most prominent, APOE, of which the ɛ4 allele increases risk in a dose-dependent manner. A breakthrough discovery enabled the creation of human induced pluripotent stem cells (hiPSCs) that can be differentiated into various brain cell types, facilitating AD research in genetically human models. Herein, we provide a brief background on AD in the context of APOE susceptibility and feature work employing hiPSC-derived brain cell and tissue models to interrogate the contribution of APOE in driving AD pathology. Such models have delivered crucial insights into cellular mechanisms and cell type-specific roles underlying the perturbed biological functions that trigger pathogenic cascades and propagate neurodegeneration. Collectively, hiPSC-based models are envisioned to be an impactful platform for uncovering fundamental AD understanding, with high translational value toward AD drug discovery and testing.
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Affiliation(s)
- Rebecca L Pinals
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Li-Huei Tsai
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA .,Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.,Broad Institute of Harvard and MIT, Cambridge, MA, USA
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19
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Pandit S. 1 H, 15 N and 13 C chemical shift assignments of the N-terminal domain of the two isoforms of the human apolipoprotein E. BIOMOLECULAR NMR ASSIGNMENTS 2022; 16:191-196. [PMID: 35451799 DOI: 10.1007/s12104-022-10078-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/10/2022] [Indexed: 06/14/2023]
Abstract
Apolipoprotein E (ApoE) is one of the major lipid transporters in humans. It is also implicated in pathological conditions like Alzheimer's and cardiovascular diseases. The N-terminal domain of ApoE binds low-density lipoprotein receptors (LDLR) while the C-terminal domain binds to the lipid. I report the backbone and aliphatic side-chain NMR chemical shifts of the N-terminal domain of two isoforms of ApoE, namely ApoE3 NTD (BMRB No. 51,122) and ApoE4 NTD (BMRB No. 51,123) at pH 3.5 (20 °C).
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Affiliation(s)
- Subhendu Pandit
- Tata Institute of Fundamental Research, 36/P, Gopanpally Village, Serilingampally Mandal, Ranga Reddy District, 500107, Hyderabad, India.
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20
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Chen J, Zhou Z, Luo S, Liu G, Xiang J, Tian Z. Progress of advanced nanomaterials in diagnosis of neurodegenerative diseases. Biosens Bioelectron 2022; 217:114717. [PMID: 36179434 DOI: 10.1016/j.bios.2022.114717] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/25/2022] [Accepted: 09/10/2022] [Indexed: 12/22/2022]
Abstract
Neurodegenerative diseases (NDDs) encompass a wide range of clinically and pathologically diverse diseases characterized by progressive long-term cognitive decline, memory and function loss in daily life. Due to the lack of effective drugs and therapeutic strategies for preventing or delaying neurodegenerative progression, it is urgent to diagnose NDDs as early and accurately as possible. Nanomaterials, emerged as one of the most promising materials in the 21st century, have been widely applied and play a significant role in diagnosis and treatment of NDDs because of their remarkable properties including stability, prominent biocompatibility, unique structure, novel physical and chemical characteristics. In this review, we outlined general strategies for the application of different types of advanced materials in early and staged diagnosis of NDDs in vivo and in vitro. According to applied technology, in vivo research mainly involves magnetic resonance, fluorescence, and surface enhanced Raman imaging on structures of brain tissues, cerebral vessels and related distributions of biomarkers. In vitro research is focused on the detection of fluid biomarkers in cerebrospinal fluid and peripheral blood based on fluorescence, electrochemical, Raman and surface plasmon resonance techniques. Finally, we discussed the current challenges and future perspectives of biomarker-based NDDs diagnosis as well as potential applications regarding advanced nanomaterials.
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Affiliation(s)
- Jia Chen
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China
| | - Zhifang Zhou
- State Key Laboratory of Marine Environmental Science, Fujian Provincial Key Laboratory for Coastal Ecology and Environmental Studies, Center for Marine Environmental Chemistry & Toxicology, College of the Environment and Ecology, Xiamen University, Xiamen, 361102, China
| | - Siheng Luo
- State Key Laboratory of Marine Environmental Science, Fujian Provincial Key Laboratory for Coastal Ecology and Environmental Studies, Center for Marine Environmental Chemistry & Toxicology, College of the Environment and Ecology, Xiamen University, Xiamen, 361102, China
| | - Guokun Liu
- State Key Laboratory of Marine Environmental Science, Fujian Provincial Key Laboratory for Coastal Ecology and Environmental Studies, Center for Marine Environmental Chemistry & Toxicology, College of the Environment and Ecology, Xiamen University, Xiamen, 361102, China
| | - Juan Xiang
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410083, PR China.
| | - Zhongqun Tian
- State Key Laboratory for Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, China.
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21
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Relationship between Brain Metabolic Disorders and Cognitive Impairment: LDL Receptor Defect. Int J Mol Sci 2022; 23:ijms23158384. [PMID: 35955522 PMCID: PMC9369234 DOI: 10.3390/ijms23158384] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 02/07/2023] Open
Abstract
The low-density-lipoprotein receptor (LDLr) removes low-density lipoprotein (LDL), an endovascular transporter that carries cholesterol from the bloodstream to peripheral tissues. The maintenance of cholesterol content in the brain, which is important to protect brain function, is affected by LDLr. LDLr co-localizes with the insulin receptor and complements the internalization of LDL. In LDLr deficiency, LDL blood levels and insulin resistance increase, leading to abnormal cholesterol control and cognitive deficits in atherosclerosis. Defects in brain cholesterol metabolism lead to neuroinflammation and blood–brain-barrier (BBB) degradation. Moreover, interactions between endoplasmic reticulum stress (ER stress) and mitochondria are induced by ox-LDL accumulation, apolipoprotein E (ApoE) regulates the levels of amyloid beta (Aβ) in the brain, and hypoxia is induced by apoptosis induced by the LDLr defect. This review summarizes the association between neurodegenerative brain disease and typical cognitive deficits.
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22
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Drummond E, Kavanagh T, Pires G, Marta-Ariza M, Kanshin E, Nayak S, Faustin A, Berdah V, Ueberheide B, Wisniewski T. The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome. Acta Neuropathol Commun 2022; 10:53. [PMID: 35418158 PMCID: PMC9008934 DOI: 10.1186/s40478-022-01356-1] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022] Open
Abstract
Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC-MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.
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Affiliation(s)
- Eleanor Drummond
- Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, 94 Mallett Street, Camperdown, NSW, Australia.
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA.
| | - Tomas Kavanagh
- Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, 94 Mallett Street, Camperdown, NSW, Australia
| | - Geoffrey Pires
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA
| | - Mitchell Marta-Ariza
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA
| | - Evgeny Kanshin
- Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY, USA
| | - Shruti Nayak
- Merck & Co., Inc, Computational & Structural Chemistry, Kenilworth, NJ, USA
| | - Arline Faustin
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA
| | - Valentin Berdah
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA
| | - Beatrix Ueberheide
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA
- Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Thomas Wisniewski
- Centre for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, Science Building, Rm 1017, 435 East 30th Street, New York, NY, 10016, USA.
- Departments of Pathology and Psychiatry, Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA.
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23
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Aguilar-Pineda JA, Paco-Coralla SG, Febres-Molina C, Gamero-Begazo PL, Shrivastava P, Vera-López KJ, Davila-Del-Carpio G, López-C P, Gómez B, Lino Cardenas CL. In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4–Amyloid-Beta (Aβ) Complex at Different pH Conditions. Biomolecules 2022; 12:biom12040499. [PMID: 35454088 PMCID: PMC9027285 DOI: 10.3390/biom12040499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022] Open
Abstract
Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer’s disease. Several studies have shown that ApoE4-Amyloid β (Aβ) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical Aβ levels, as well as decreases the number of activated astrocytes around Aβ plaques. However, the interactions between enoxaparin and the ApoE4-Aβ proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-Aβ interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-Aβ interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-Aβ complex formation.
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Affiliation(s)
- Jorge Alberto Aguilar-Pineda
- Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (S.G.P.-C.); (P.S.); (K.J.V.-L.); (G.D.-D.-C.)
- Centro de Investigación en Ingeniería Molecular—CIIM, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (P.L.G.-B.); (B.G.)
- Correspondence: (J.A.A.-P.); (C.L.L.C.)
| | - Silvana G. Paco-Coralla
- Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (S.G.P.-C.); (P.S.); (K.J.V.-L.); (G.D.-D.-C.)
| | - Camilo Febres-Molina
- Doctorado en Fisicoquímica Molecular, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago 8370134, Chile;
| | - Pamela L. Gamero-Begazo
- Centro de Investigación en Ingeniería Molecular—CIIM, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (P.L.G.-B.); (B.G.)
| | - Pallavi Shrivastava
- Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (S.G.P.-C.); (P.S.); (K.J.V.-L.); (G.D.-D.-C.)
| | - Karin J. Vera-López
- Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (S.G.P.-C.); (P.S.); (K.J.V.-L.); (G.D.-D.-C.)
- Facultad de Ciencias Farmacéuticas, Bioquímicas y Biotecnológicas, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru
| | - Gonzalo Davila-Del-Carpio
- Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (S.G.P.-C.); (P.S.); (K.J.V.-L.); (G.D.-D.-C.)
- Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru;
| | - Patricia López-C
- Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru;
| | - Badhin Gómez
- Centro de Investigación en Ingeniería Molecular—CIIM, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru; (P.L.G.-B.); (B.G.)
- Facultad de Ciencias Farmacéuticas, Bioquímicas y Biotecnológicas, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, Peru
| | - Christian L. Lino Cardenas
- Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA
- Correspondence: (J.A.A.-P.); (C.L.L.C.)
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24
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Vecchio FL, Bisceglia P, Imbimbo BP, Lozupone M, Latino RR, Resta E, Leone M, Solfrizzi V, Greco A, Daniele A, Watling M, Panza F, Seripa D. Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease? Ther Adv Chronic Dis 2022; 13:20406223221081605. [PMID: 35321401 PMCID: PMC8935560 DOI: 10.1177/20406223221081605] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/28/2022] [Indexed: 11/17/2022] Open
Abstract
Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE (APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.
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Affiliation(s)
- Filomena Lo Vecchio
- Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia 71013, Italy
| | - Paola Bisceglia
- Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | | | - Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Raffaela Rita Latino
- Complex Structure of Neurology, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Emanuela Resta
- Translational Medicine and Management of Health Systems, University of Foggia, Foggia, Italy
| | - Maurizio Leone
- Complex Structure of Neurology, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Vincenzo Solfrizzi
- ‘Cesare Frugoni’ Internal and Geriatric Medicine and Memory Unit, University of Bari ‘Aldo Moro’, Bari, Italy
| | - Antonio Greco
- Department of Neuroscience, Catholic University of the Sacred Heart, Rome, Italy; Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | | | - Mark Watling
- CNS & Pain Department, TranScrip Ltd, Reading, UK
| | - Francesco Panza
- Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
- Population Health Unit, Healthy Aging Phenotypes Research Unit, ‘Salus in Apulia Study’, National Institute of Gastroenterology ‘Saverio de Bellis’, Research Hospital, Castellana Grotte, Bari 70013, Italy
| | - Davide Seripa
- Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Hematology and Stem Cell Transplant Unit, ‘Vito Fazzi’ Hospital, Lecce, Italy
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25
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Gharibyan AL, Wasana Jayaweera S, Lehmann M, Anan I, Olofsson A. Endogenous Human Proteins Interfering with Amyloid Formation. Biomolecules 2022; 12:biom12030446. [PMID: 35327638 PMCID: PMC8946693 DOI: 10.3390/biom12030446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 01/09/2023] Open
Abstract
Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.
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Affiliation(s)
- Anna L. Gharibyan
- Department of Clinical Microbiology, Umeå University, 901 87 Umeå, Sweden;
- Correspondence: (A.L.G.); (A.O.)
| | | | - Manuela Lehmann
- Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå, Sweden; (M.L.); (I.A.)
| | - Intissar Anan
- Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå, Sweden; (M.L.); (I.A.)
| | - Anders Olofsson
- Department of Clinical Microbiology, Umeå University, 901 87 Umeå, Sweden;
- Correspondence: (A.L.G.); (A.O.)
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Mahan TE, Wang C, Bao X, Choudhury A, Ulrich JD, Holtzman DM. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener 2022; 17:13. [PMID: 35109920 PMCID: PMC8811969 DOI: 10.1186/s13024-022-00516-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 01/13/2022] [Indexed: 12/11/2022] Open
Abstract
Background One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects. Supplementary Information The online version contains supplementary material available at 10.1186/s13024-022-00516-0.
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Affiliation(s)
- Thomas E Mahan
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA
| | - Chao Wang
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA
| | - Xin Bao
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA
| | - Ankit Choudhury
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA
| | - Jason D Ulrich
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
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Lv S, Zhou X, Li YM, Yang T, Zhang SJ, Wang Y, Jia SH, Peng DT. N6-methyladenine-modified DNA was decreased in Alzheimer’s disease patients. World J Clin Cases 2022; 10:448-457. [PMID: 35097069 PMCID: PMC8771380 DOI: 10.12998/wjcc.v10.i2.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/19/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In recent years, the prevalence of Alzheimer’s disease (AD) has increased, which places a great burden on society and families and creates considerable challenges for medical services. N6-methyladenine (m6A) deoxyribonucleic acid (DNA) adenine methylation is a novel biomarker and is abundant in the brain, but less common in AD. We support to analyze the relationship between DNA m6A and cognition in patients with AD and normal controls (NCs) in China.
AIM To analyze the relationship between the novel m6A DNA and cognition in patients with AD and NCs in China.
METHODS A total of 179 AD patients (mean age 71.60 ± 9.89 years; males: 91; females: 88) and 147 NCs (mean age 69.59 ± 11.22 years; males: 77; females: 70) who were age- and sex-matched were included in our study. All subjects underwent neuropsychological scale assessment and magnetic resonance imaging examination. Apolipoprotein E (APOE) genotypes were measured through agarose gel electrophoresis. Global m6A levels were evaluated by a MethylFlash m6A DNA Methylation ELISA Kit (colorimetric). Global m6A levels in total DNA from ten AD patients with 18F-AV-45 (florbetapir) positron emission tomography (PET) positivity and ten NCs with PET negativity were analyzed by dot blotting to determine the results.
RESULTS Our ELISA results showed that the global m6A DNA levels in peripheral blood were different between patients with AD and NCs (P = 0.002; < 0.05). And ten AD patients who were PET positive and ten NCs who were PET negative also showed the same results through dot blotting. There were significant differences between the two groups, which indicated that the leukocyte m6A DNA levels were different (P = 0.005; < 0.05). The m6A level was approximately 8.33% lower in AD patients than in NCs (mean 0.011 ± 0.006 vs 0.012 ± 0.005). A significant correlation was found between the Montreal Cognitive Assessment score and the peripheral blood m6A level in the tested population (r = 0.143, P = 0.01; < 0.05). However, no relationship was found with APOE ε4 (P = 0.633, > 0.05). Further studies should be performed to validate these findings.
CONCLUSION Our results show that reduced global m6A DNA methylation levels are significantly lower in AD patients than in NCs by approximately 8.33% in China.
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Affiliation(s)
- Shuang Lv
- Department of Neurology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao Zhou
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
- Department of Neurology, Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100029, China
| | - Yi-Ming Li
- Department of Cardiovascular, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Tao Yang
- Department of Geriatric, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
| | - Shu-Juan Zhang
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yu Wang
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Hong Jia
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Dan-Tao Peng
- Department of Neurology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China
- Department of Neurology, Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100029, China
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Parhizkar S, Holtzman DM. APOE mediated neuroinflammation and neurodegeneration in Alzheimer's disease. Semin Immunol 2022; 59:101594. [PMID: 35232622 PMCID: PMC9411266 DOI: 10.1016/j.smim.2022.101594] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/14/2022] [Indexed: 01/15/2023]
Abstract
Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer's disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD.
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Affiliation(s)
- Samira Parhizkar
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA
| | - David M. Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA
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29
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Blank N, Mayer M, Mass E. The development and physiological and pathophysiological functions of resident macrophages and glial cells. Adv Immunol 2021; 151:1-47. [PMID: 34656287 DOI: 10.1016/bs.ai.2021.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the past, brain function and the onset and progression of neurological diseases have been studied in a neuron-centric manner. However, in recent years the focus of many neuroscientists has shifted to other cell types that promote neurodevelopment and contribute to the functionality of neuronal networks in health and disease. Particularly microglia and astrocytes have been implicated in actively contributing to and controlling neuronal development, neuroinflammation, and neurodegeneration. Here, we summarize the development of brain-resident macrophages and astrocytes and their core functions in the developing brain. We discuss their contribution and intercellular crosstalk during tissue homeostasis and pathophysiology. We argue that in-depth knowledge of non-neuronal cells in the brain could provide novel therapeutic targets to reverse or contain neurological diseases.
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Affiliation(s)
- Nelli Blank
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
| | - Marina Mayer
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Elvira Mass
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
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30
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Ahmed MM, Johnson NR, Boyd TD, Coughlan C, Chial HJ, Potter H. Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners? Front Aging Neurosci 2021; 13:718426. [PMID: 34603007 PMCID: PMC8481947 DOI: 10.3389/fnagi.2021.718426] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
Innate immune system activation and inflammation are associated with and may contribute to clinical outcomes in people with Down syndrome (DS), neurodegenerative diseases such as Alzheimer's disease (AD), and normal aging. In addition to serving as potential diagnostic biomarkers, innate immune system activation and inflammation may play a contributing or causal role in these conditions, leading to the hypothesis that effective therapies should seek to dampen their effects. However, recent intervention studies with the innate immune system activator granulocyte-macrophage colony-stimulating factor (GM-CSF) in animal models of DS, AD, and normal aging, and in an AD clinical trial suggest that activating the innate immune system and inflammation may instead be therapeutic. We consider evidence that DS, AD, and normal aging are accompanied by innate immune system activation and inflammation and discuss whether and when during the disease process it may be therapeutically beneficial to suppress or promote such activation.
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Affiliation(s)
- Md. Mahiuddin Ahmed
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Noah R. Johnson
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Timothy D. Boyd
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Partner Therapeutics, Inc., Lexington, MA, United States
| | - Christina Coughlan
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heidi J. Chial
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Huntington Potter
- Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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31
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Chai AB, Lam HHJ, Kockx M, Gelissen IC. Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158980. [PMID: 34044125 DOI: 10.1016/j.bbalip.2021.158980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/16/2021] [Accepted: 05/20/2021] [Indexed: 12/28/2022]
Abstract
Since the identification of the apolipoprotein E (apoE) *ε4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-β (Aβ) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic Aβ peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the Aβ processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired Aβ clearance, however data regarding Aβ synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with Aβ. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform.
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Affiliation(s)
- Amanda B Chai
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Hin Hei Julian Lam
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Maaike Kockx
- ANZAC Research Institute, Concord Repatriation General Hospital, University of Sydney, Concord, NSW 2139, Australia
| | - Ingrid C Gelissen
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
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Abstract
Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Apart from the fibril protein, amyloid deposits frequently enclose non-fibrillar constituents. In routine diagnostics, we noticed the presence of complement 9 (C9) in amyloid. Based on this observation, we systematically explored the occurrence of C9 in amyloid. Apolipoprotein E (apoE), caspase 3 and complement 3 (C3) served as controls. From the Amyloid Registry Kiel, we retrieved 118 formalin-fixed and paraffin-embedded tissue samples, including eight different amyloid- and 18 different tissue types. The expression patterns were assessed immunohistochemically in relation to amyloid deposits. A literature search on proteomic data was performed. Amyloid deposits stained for C9 and apoE in 117 (99.2%) and 112 of 118 (94.9%) cases, respectively. A homogeneous immunostaining of the entire amyloid deposits was found in 75.4% (C9) and 61.9% (apoE) of the cases. Caspase 3 and C3 were present only in 22 (19.3%) of 114 and 20 (36%) of 55 assessable cases, respectively. Caspase 3 and C3 immunostaining rarely covered substantial areas of the amyloid deposits. The literature search on proteomic data confirmed the frequent detection of apoE and the occurrence of C9 and C3 in amyloid deposits. No data were found regarding caspase 3. Our findings demonstrate the ubiquitous, spatial and specific enrichment of C9 in amyloid deposits irrespective of amyloid-, organ- or tissue type. Our findings lend support to the hypothesis that amyloidosis might activate the complement cascade, which could lead to the formation of the membrane attack complex and cell death.
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Affiliation(s)
- Annelie Lux
- Department of Pathology, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Juliane Gottwald
- Department of Pathology, Christian-Albrechts-University Kiel, Kiel, Germany
| | | | - Christoph Daniel
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University Kiel, Kiel, Germany
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33
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Bai Y, Wan W, Huang Y, Jin W, Lyu H, Xia Q, Dong X, Gao Z, Liu Y. Quantitative interrogation of protein co-aggregation using multi-color fluorogenic protein aggregation sensors. Chem Sci 2021; 12:8468-8476. [PMID: 34221329 PMCID: PMC8221170 DOI: 10.1039/d1sc01122g] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/19/2021] [Indexed: 12/27/2022] Open
Abstract
Co-aggregation of multiple pathogenic proteins is common in neurodegenerative diseases but deconvolution of such biochemical process is challenging. Herein, we developed a dual-color fluorogenic thermal shift assay to simultaneously report on the aggregation of two different proteins and quantitatively study their thermodynamic stability during co-aggregation. Expansion of spectral coverage was first achieved by developing multi-color fluorogenic protein aggregation sensors. Orthogonal detection was enabled by conjugating sensors of minimal fluorescence crosstalk to two different proteins via sortase-tag technology. Using this assay, we quantified shifts in melting temperatures in a heterozygous model protein system, revealing that the thermodynamic stability of wild-type proteins was significantly compromised by the mutant ones but not vice versa. We also examined how small molecule ligands selectively and differentially interfere with such interplay. Finally, we demonstrated these sensors are suited to visualize how different proteins exert influence on each other upon their co-aggregation in live cells.
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Affiliation(s)
- Yulong Bai
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
- University of Chinese Academy of Sciences Beijing 100049 China
| | - Wang Wan
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
| | - Yanan Huang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
| | - Wenhan Jin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
| | - Haochen Lyu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
| | - Qiuxuan Xia
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
- University of Chinese Academy of Sciences Beijing 100049 China
| | - Xuepeng Dong
- The Second Hospital of Dalian Medical University 467 Zhongshan Road Dalian 116044 China
| | - Zhenming Gao
- The Second Hospital of Dalian Medical University 467 Zhongshan Road Dalian 116044 China
| | - Yu Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road Dalian 116023 China
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Kemiklioglu E, Tuncgovde EB, Ozsarlak-Sozer G. Development of liquid crystal biosensor for the detection of amyloid beta-42 levels associated with Alzheimer's disease. J Biosci Bioeng 2021; 132:88-94. [PMID: 33934978 DOI: 10.1016/j.jbiosc.2021.03.016] [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: 12/23/2020] [Revised: 03/04/2021] [Accepted: 03/26/2021] [Indexed: 12/27/2022]
Abstract
This study represents the development of a biosensor which is based on the liquid crystal (LC) orientation as a function of the peptide concentration to detect an amyloid-beta-42 (Aβ42) antibody-antigen binding events. The Aβ42 peptide binds to the Aβ42 antibody forming an immunocomplex which is immobilized on the Dimethyloctadecyl[3-(trimethoxysilyl)propyl] ammonium chloride (DMOAP) coated surface. The disturbed orientation of LCs as a result of the binding of the formed immunocomplex was observed using the polarized optical microscope (POM) as a function of decreasing Aβ42 peptide concentration from 1000 to 1 pg/ml. The concentration, as low as 1 pg/ml of Aβ42 peptide was able to be successfully detected in our system. Apolipoprotein E4 (ApoE4), that specifically bound to the Aβ42 peptide, was added into the system and a remarkable change in reflection spectra of samples was observed with increasing Aβ42 peptide concentration. The concentration of ApoE4 protein was detected in the range of 0.1-30 nM by this system due to the interaction between the two proteins.
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Affiliation(s)
- Emine Kemiklioglu
- Bioengineering Department, Manisa Celal Bayar University, Yunusemre, Manisa 45140, Turkey.
| | | | - Gonen Ozsarlak-Sozer
- Department of Pharmacology, Faculty of Pharmacy, Ege University, Bornova, İzmir 35100, Turkey
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Cercy SP. Pericytes and the Neurovascular Unit: The Critical Nexus of Alzheimer Disease Pathogenesis? EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021. [DOI: 10.14218/erhm.2020.00062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Wasana Jayaweera S, Surano S, Pettersson N, Oskarsson E, Lettius L, Gharibyan AL, Anan I, Olofsson A. Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation. Biomolecules 2021; 11:biom11030411. [PMID: 33802170 PMCID: PMC8001701 DOI: 10.3390/biom11030411] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/04/2021] [Indexed: 12/18/2022] Open
Abstract
Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.
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Affiliation(s)
- Sanduni Wasana Jayaweera
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Solmaz Surano
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Nina Pettersson
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Elvira Oskarsson
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Lovisa Lettius
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Anna L. Gharibyan
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
| | - Intissar Anan
- Wallenberg Centre for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden;
| | - Anders Olofsson
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; (S.W.J.); (S.S.); (N.P.); (E.O.); (L.L.); (A.L.G.)
- Correspondence: ; Tel.: +46-70-354-3301
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Liu Y, Song JH, Xu W, Hou XH, Li JQ, Yu JT, Tan L, Chi S, and Alzheimer’s Disease Neuroimaging Initiative. The Associations of Cerebrospinal Fluid ApoE and Biomarkers of Alzheimer's Disease: Exploring Interactions With Sex. Front Neurosci 2021; 15:633576. [PMID: 33746700 PMCID: PMC7968417 DOI: 10.3389/fnins.2021.633576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/25/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Sex-related difference in Alzheimer's disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD. OBJECTIVE We aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes). METHODS Data of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex-ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers. RESULTS Significant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-β (Aβ): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aβ (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aβ: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally. CONCLUSION The associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.
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Affiliation(s)
- Ying Liu
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing-Hui Song
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Xu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Xiao-He Hou
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jie-Qiong Li
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jin-Tai Yu
- Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Song Chi
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Mehla J, Gupta P, Pahuja M, Diwan D, Diksha D. Indian Medicinal Herbs and Formulations for Alzheimer's Disease, from Traditional Knowledge to Scientific Assessment. Brain Sci 2020; 10:E964. [PMID: 33321899 PMCID: PMC7764187 DOI: 10.3390/brainsci10120964] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/27/2020] [Accepted: 12/07/2020] [Indexed: 12/31/2022] Open
Abstract
Cognitive impairment, associated with ageing, stress, hypertension and various neurodegenerative disorders including Parkinson's disease and epilepsy, is a major health issue. The present review focuses on Alzheimer's disease (AD), since it is the most important cause of cognitive impairment. It is characterized by progressive memory loss, language deficits, depression, agitation, mood disturbances and psychosis. Although the hallmarks of AD are cholinergic dysfunction, β-amyloid plaques and neurofibrillary tangle formation, it is also associated with derangement of other neurotransmitters, elevated levels of advanced glycation end products, oxidative damage, neuroinflammation, genetic and environmental factors. On one hand, this complex etiopathology makes a response to commonly used drugs such as donepezil, rivastigmine, galantamine and memantine less predictable and often unsatisfactory. On the other hand, it supports the use of herbal medicines due to their nonspecific antioxidant and anti-inflammatory activity and specific cholinesterase inhibitory activity. The popularity of herbal medicines is also increasing due to their perceived effectiveness, safety and affordability. In the present article, the experimental and clinical evidence have been reviewed for various Indian herbal medicines such as Centella asiatica, Bacopa monnieri, Curcuma longa, Clitoria ternatea, Withania somnifera, Celastrus paniculatus, Evolvulus alsinoides, Desmodium gangeticum, Eclipta alba, Moringa oleifera and Convolvulus pluricaulis, which have shown potential in cognitive impairment. Some commonly available herbal formulations for memory impairment in India have also been reviewed.
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Affiliation(s)
- Jogender Mehla
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Pooja Gupta
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Monika Pahuja
- Division of Basic Medical Sciences, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, V. Ramalingaswamy Bhawan, New Delhi 110029, India;
| | - Deepti Diwan
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Diksha Diksha
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India;
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Fani L, Ahmad S, Ikram MK, Ghanbari M, Ikram MA. Immunity and amyloid beta, total tau and neurofilament light chain: Findings from a community-based cohort study. Alzheimers Dement 2020; 17:446-456. [PMID: 33215849 PMCID: PMC8048997 DOI: 10.1002/alz.12212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/20/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022]
Abstract
Introduction We investigated how components of immunity relate to biomarkers of Alzheimer's disease (AD) in plasma and explored the influence of AD genetic risk factors in the population‐based Rotterdam Study. Methods In 7397 persons, we calculated the granulocyte‐to‐lymphocyte ratio (GLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune‐inflammation index (SII). In 3615 of these persons, plasma amyloid‐beta (Aβ)42 and Aβ40 were measured. Next, we constructed an overall genetic risk score (GRS) based on genome‐wide significant variants, both including and excluding APOE ε4. Results All innate immunity phenotypes were related to higher Aβ, most strongly with a doubling in GLR leading to a 1.9% higher Aβ42 (95% confidence interval [95% CI] 0.4 to 3.3%) and 3.2% higher Aβ40 (95% CI 2.0 to 4.3%). Higher AD GRS including APOE ε4 was associated with higher immunity markers. Discussion Higher levels of immunity markers were associated with higher Aβ in plasma. Participants with a higher genetic predisposition to AD had higher immunity markers, where these effects were mainly driven by APOE ε4.
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Affiliation(s)
- Lana Fani
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Shahzad Ahmad
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.,Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - M Kamran Ikram
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.,Erasmus MC, Department of Neurology, the Netherlands
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
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Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis. Neuron 2020; 109:205-221. [PMID: 33176118 DOI: 10.1016/j.neuron.2020.10.008] [Citation(s) in RCA: 170] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 01/02/2023]
Abstract
Apolipoprotein E (ApoE) is of great interest due to its role as a cholesterol/lipid transporter in the central nervous system (CNS) and as the most influential genetic risk factor for Alzheimer disease (AD). Work over the last four decades has given us important insights into the structure of ApoE and how this might impact the neuropathology and pathogenesis of AD. In this review, we highlight the history and progress in the structural and molecular understanding of ApoE and discuss how these studies on ApoE have illuminated the physiology of ApoE, receptor binding, and interaction with amyloid-β (Aβ). We also identify future areas of study needed to advance our understanding of how ApoE influences neurodegeneration.
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Affiliation(s)
- Yun Chen
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA; The Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA
| | - Michael R Strickland
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA; The Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA
| | - Andrea Soranno
- Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, USA; Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO, USA
| | - David M Holtzman
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA; Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
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Johnson ECB, Ho K, Yu GQ, Das M, Sanchez PE, Djukic B, Lopez I, Yu X, Gill M, Zhang W, Paz JT, Palop JJ, Mucke L. Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1. Mol Neurodegener 2020; 15:53. [PMID: 32921309 PMCID: PMC7489007 DOI: 10.1186/s13024-020-00393-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. METHODS To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. RESULTS Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. CONCLUSIONS hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.
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Affiliation(s)
- Erik C. B. Johnson
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Kaitlyn Ho
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Gui-Qiu Yu
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Melanie Das
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Pascal E. Sanchez
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Biljana Djukic
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Isabel Lopez
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Xinxing Yu
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Michael Gill
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Weiping Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Institute of Endocrinology, Tianjin Medical University Metabolic Diseases Hospital, Tianjin, China
| | - Jeanne T. Paz
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Jorge J. Palop
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Lennart Mucke
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
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Toyos-Rodríguez C, García-Alonso FJ, de la Escosura-Muñiz A. Electrochemical Biosensors Based on Nanomaterials for Early Detection of Alzheimer's Disease. SENSORS (BASEL, SWITZERLAND) 2020; 20:E4748. [PMID: 32842632 PMCID: PMC7506792 DOI: 10.3390/s20174748] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is an untreatable neurodegenerative disease that initially manifests as difficulty to remember recent events and gradually progresses to cognitive impairment. The incidence of AD is growing yearly as life expectancy increases, thus early detection is essential to ensure a better quality of life for diagnosed patients. To reach that purpose, electrochemical biosensing has emerged as a cost-effective alternative to traditional diagnostic techniques, due to its high sensitivity and selectivity. Of special relevance is the incorporation of nanomaterials in biosensors, as they contribute to enhance electron transfer while promoting the immobilization of biological recognition elements. Moreover, nanomaterials have also been employed as labels, due to their unique electroactive and electrocatalytic properties. The aim of this review is to add value in the advances achieved in the detection of AD biomarkers, the strategies followed for the incorporation of nanomaterials and its effect in biosensors performance.
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Affiliation(s)
- Celia Toyos-Rodríguez
- NanoBioAnalysis Group-Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, 33006 Oviedo, Spain;
- Biotechnology Institute of Asturias, University of Oviedo, Santiago Gascon Building, 33006 Oviedo, Spain;
| | - Francisco Javier García-Alonso
- Biotechnology Institute of Asturias, University of Oviedo, Santiago Gascon Building, 33006 Oviedo, Spain;
- NanoBioAnalysis Group-Department of Organic and Inorganic Chemistry, University of Oviedo, Julián Clavería 8, 33006 Oviedo, Spain
| | - Alfredo de la Escosura-Muñiz
- NanoBioAnalysis Group-Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, 33006 Oviedo, Spain;
- Biotechnology Institute of Asturias, University of Oviedo, Santiago Gascon Building, 33006 Oviedo, Spain;
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The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Mol Neurobiol 2020; 57:3803-3813. [PMID: 32572762 DOI: 10.1007/s12035-020-01988-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 06/10/2020] [Indexed: 10/24/2022]
Abstract
Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR), and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer's disease (AD), where apoE is involved in neuronal uptake and accumulation of Aβ42, eventually cascading into neurodegeneration, synaptic dysfunction, and ultimately, dementia. We hypothesize that the intact Sigma-2 receptor complex-TMEM97, PGRMC1, and LDLR-is necessary for internalization of apoE and Aβ42 monomers (mAβ42) and oligomers (oAβ42), and the disruption of the receptor complex inhibits uptake. The results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4. The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons. The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal Aβ42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.
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Vogelgsang J, Vukovich R, Wedekind D, Wiltfang J. Higher Level of Mismatch in APOEε4 Carriers for Amyloid-Beta Peptide Alzheimer's Disease Biomarkers in Cerebrospinal Fluid. ASN Neuro 2020; 11:1759091419845524. [PMID: 31104469 PMCID: PMC6535906 DOI: 10.1177/1759091419845524] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cerebrospinal fluid (CSF) biomarkers are widely used in the diagnosis of dementia. Even though there is a causal correlation between apolipoprotein E ( APOE) genotype and amyloid-beta (Aβ), the determination of APOE is currently not supported by national or international guidelines. We compared parallel measured CSF biomarkers of two independent laboratories from 126 patients who underwent clinical dementia diagnostics regarding the APOE genotype. APOE ε4 reduces Aβ1-42 (Aβ42) and Aβ42 to Aβ 1-40 ratio (Aβ42/40) but not total Tau or phospho-181 Tau CSF levels. Higher discordance rates were observed for Aβ42 and subsequently for Aβ42/40 in APOE ε4 carriers compared with noncarriers, and the correlation between the two laboratories was significantly lower for Aβ42 in APOE ε4 positive patients compared with patients without APOE ε4. These observations demonstrate that the evaluation of CSF Aβ biomarkers needs to be interpreted carefully in the clinical context. Different immunoassays, disparate cutoff values, and APOE should be respected.
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Affiliation(s)
- Jonathan Vogelgsang
- 1 Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Germany
| | - Ruth Vukovich
- 1 Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Germany
| | - Dirk Wedekind
- 1 Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Germany
| | - Jens Wiltfang
- 1 Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Germany.,2 German Center for Neurodegenerative Diseases, Goettingen, Germany.,3 iBiMED, Medical Science Department, University of Aveiro, Portugal
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Wisniewski T, Drummond E. APOE-amyloid interaction: Therapeutic targets. Neurobiol Dis 2020; 138:104784. [PMID: 32027932 PMCID: PMC7118587 DOI: 10.1016/j.nbd.2020.104784] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/22/2020] [Accepted: 01/31/2020] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that is growing in prevalence globally. It is the only major cause of death without any effective pharmacological means to treat or slow progression. Inheritance of the ε4 allele of the Apolipoprotein (APO) E gene is the strongest genetic risk factor for late-onset AD. The interaction between APOE and amyloid β (Aβ) plays a key role in AD pathogenesis. The APOE-Aβ interaction regulates Aβ aggregation and clearance and therefore directly influences the development of amyloid plaques, congophilic amyloid angiopathy and subsequent tau related pathology. Relatively few AD therapeutic approaches have directly targeted the APOE-Aβ interaction thus far. Here we review the critical role of APOE in the pathogenesis of AD and some of the most promising therapeutic approaches that focus on the APOE-Aβ interaction.
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Affiliation(s)
- Thomas Wisniewski
- Departments of Neurology, Pathology and Psychiatry, Center for Cognitive Neurology, NYU School of Medicine, Science Building, Rm 1017, 435 East 30(th) Street, New York, NY 10016, USA.
| | - Eleanor Drummond
- Brain & Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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Gharibyan AL, Islam T, Pettersson N, Golchin SA, Lundgren J, Johansson G, Genot M, Schultz N, Wennström M, Olofsson A. Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity. Biomolecules 2020; 10:biom10010134. [PMID: 31947546 PMCID: PMC7022431 DOI: 10.3390/biom10010134] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/10/2020] [Accepted: 01/12/2020] [Indexed: 02/06/2023] Open
Abstract
Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.
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Affiliation(s)
- Anna L. Gharibyan
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
- Correspondence: (A.L.G.); (A.O.); Tel.: +46-73-912-54-94 (A.L.G.); +46-70-354-33-01 (A.O.)
| | - Tohidul Islam
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Nina Pettersson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Solmaz A. Golchin
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Johanna Lundgren
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Gabriella Johansson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Mélany Genot
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
| | - Nina Schultz
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden; (N.S.); (M.W.)
| | - Malin Wennström
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden; (N.S.); (M.W.)
| | - Anders Olofsson
- Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden; (T.I.); (N.P.); (S.A.G.); (J.L.); (G.J.); (M.G.)
- Correspondence: (A.L.G.); (A.O.); Tel.: +46-73-912-54-94 (A.L.G.); +46-70-354-33-01 (A.O.)
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APOE in the normal brain. Neurobiol Dis 2020; 136:104724. [PMID: 31911114 DOI: 10.1016/j.nbd.2019.104724] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/19/2019] [Accepted: 12/31/2019] [Indexed: 12/25/2022] Open
Abstract
The APOE4 protein affects the primary neuropathological markers of Alzheimer's disease (AD): amyloid plaques, neurofibrillary tangles, and gliosis. These interactions have been investigated to understand the strong effect of APOE genotype on risk of AD. However, APOE genotype has strong effects on processes in normal brains, in the absence of the hallmarks of AD. We propose that CNS APOE is involved in processes in the normal brains that in later years apply specifically to processes of AD pathogenesis. We review the differences of the APOE protein found in the CNS compared to the plasma, including post-translational modifications (glycosylation, lipidation, multimer formation), focusing on ways that the common APOE isoforms differ from each other. We also review structural and functional studies of young human brains and control APOE knock-in mouse brains. These approaches demonstrate the effects of APOE genotype on microscopic neuron structure, gross brain structure, and behavior, primarily related to the hippocampal areas. By focusing on the effects of APOE genotype on normal brain function, approaches can be pursued to identify biomarkers of APOE dysfunction, to promote normal functions of the APOE4 isoform, and to prevent the accumulation of the pathologic hallmarks of AD with aging.
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Huynh TPV, Wang C, Tran AC, Tabor GT, Mahan TE, Francis CM, Finn MB, Spellman R, Manis M, Tanzi RE, Ulrich JD, Holtzman DM. Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. Mol Neurodegener 2019; 14:37. [PMID: 31623648 PMCID: PMC6796484 DOI: 10.1186/s13024-019-0337-1] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 08/30/2019] [Indexed: 11/23/2022] Open
Abstract
Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner. Electronic supplementary material The online version of this article (10.1186/s13024-019-0337-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tien-Phat V Huynh
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, USA
| | - Chao Wang
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Ainsley C Tran
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - G Travis Tabor
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Medical Scientist Training Program (MSTP), Washington University School of Medicine, St. Louis, MO, USA
| | - Thomas E Mahan
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Caroline M Francis
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Mary Beth Finn
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Rebecca Spellman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Melissa Manis
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Rudolph E Tanzi
- McCance Center for Brain Health and Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Jason D Ulrich
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
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Islam T, Gharibyan AL, Golchin SA, Pettersson N, Brännström K, Hedberg I, Virta MM, Olofsson L, Olofsson A. Apolipoprotein E impairs amyloid-β fibril elongation and maturation. FEBS J 2019; 287:1208-1219. [PMID: 31571352 DOI: 10.1111/febs.15075] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/18/2019] [Accepted: 09/27/2019] [Indexed: 01/01/2023]
Abstract
Alzheimer's disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid-binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose-dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation-dependent mechanism where free monomers are added onto a nucleus in a template-dependent manner. Using a combination of surface plasmon resonance and thioflavin-T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.
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Affiliation(s)
- Tohidul Islam
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Anna L Gharibyan
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Solmaz A Golchin
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Nina Pettersson
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | | | - Isabell Hedberg
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Merit-Miriam Virta
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Linnea Olofsson
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
| | - Anders Olofsson
- Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
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Bales KR, Paul SM. Targeting apolipoprotein E for treating Alzheimer's disease. Neurosci Lett 2019; 709:134366. [PMID: 31336138 DOI: 10.1016/j.neulet.2019.134366] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/24/2019] [Accepted: 07/02/2019] [Indexed: 01/22/2023]
Abstract
The ε4 allele of the apolipoprotein E gene represents the most widely reproduced and robust susceptibility loci for the most common late onset and sporadic forms of Alzheimer's disease. While the discovery of this now widely replicated association was reported more than 25 years ago, few therapeutic interventions that specifically target the apolipoprotein pathway in brain have emerged. Here we discuss our current understanding of apolipoprotein E biology in brain, its relationship to the pathogenesis of Alzheimer's disease and present potential future avenues for exploration that may be amenable to drug development.
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Affiliation(s)
- Kelly R Bales
- Neuroscience Discovery, Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
| | - Steven M Paul
- Karuna Therapeutics, Inc., Boston, MA, United States
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