دورية أكاديمية
APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
| العنوان: | APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology. |
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| المؤلفون: | Jin Y; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Li F; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Sonoustoun B; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Kondru NC; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Martens YA; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Qiao W; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Heckman MG; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, 32224, USA., Ikezu TC; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Li Z; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Burgess JD; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Amerna D; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., O'Leary J; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., DeTure MA; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Zhao J; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., McLean PJ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Ross OA; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Bu G; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. bu.guojun@mayo.edu., Zhao N; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. zhao.na@mayo.edu. |
| المصدر: | Acta neuropathologica [Acta Neuropathol] 2022 Jun; Vol. 143 (6), pp. 641-662. Date of Electronic Publication: 2022 Apr 26. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0412041 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0533 (Electronic) Linking ISSN: 00016322 NLM ISO Abbreviation: Acta Neuropathol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Berlin : Springer Verlag |
| مواضيع طبية MeSH: | Alzheimer Disease*/pathology , Apolipoprotein E4*/genetics , Induced Pluripotent Stem Cells*/metabolism , Lewy Body Disease*/pathology , Neurotoxicity Syndromes*, Apolipoproteins E ; Genome-Wide Association Study ; Humans ; Lewy Bodies/pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism |
| مستخلص: | Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis. How APOE4 modulates α-SYN aggregation in AD is unclear. In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity. We measured α-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (N = 469), where 54% had concomitant LB pathology (AD + LB). We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble α-SYN and found that α-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the α-SYN species (~ 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD. (© 2022. The Author(s).) |
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| معلومات مُعتمدة: | U19 AG069701 United States AG NIA NIH HHS; U54 NS110435 United States NS NINDS NIH HHS |
| فهرسة مساهمة: | Keywords: Alzheimer’s disease; Apolipoprotein E; Lewy body dementia; RT-QuIC; Seeding; α-synuclein |
| المشرفين على المادة: | 0 (ApoE protein, human) 0 (Apolipoprotein E4) 0 (Apolipoproteins E) 0 (alpha-Synuclein) 0 (tau Proteins) |
| تواريخ الأحداث: | Date Created: 20220426 Date Completed: 20220517 Latest Revision: 20220824 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC9107450 |
| DOI: | 10.1007/s00401-022-02421-8 |
| PMID: | 35471463 |
| قاعدة البيانات: | MEDLINE |
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