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APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology

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 stro...

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Autores principales: Jin, Yunjung, Li, Fuyao, Sonoustoun, Berkiye, Kondru, Naveen Chandra, Martens, Yuka A., Qiao, Wenhui, Heckman, Michael G., Ikezu, Tadafumi C., Li, Zonghua, Burgess, Jeremy D., Amerna, Danilyn, O’Leary, Justin, DeTure, Michael A., Zhao, Jing, McLean, Pamela J., Dickson, Dennis W., Ross, Owen A., Bu, Guojun, Zhao, Na
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107450/
https://www.ncbi.nlm.nih.gov/pubmed/35471463
http://dx.doi.org/10.1007/s00401-022-02421-8
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author Jin, Yunjung
Li, Fuyao
Sonoustoun, Berkiye
Kondru, Naveen Chandra
Martens, Yuka A.
Qiao, Wenhui
Heckman, Michael G.
Ikezu, Tadafumi C.
Li, Zonghua
Burgess, Jeremy D.
Amerna, Danilyn
O’Leary, Justin
DeTure, Michael A.
Zhao, Jing
McLean, Pamela J.
Dickson, Dennis W.
Ross, Owen A.
Bu, Guojun
Zhao, Na
author_facet Jin, Yunjung
Li, Fuyao
Sonoustoun, Berkiye
Kondru, Naveen Chandra
Martens, Yuka A.
Qiao, Wenhui
Heckman, Michael G.
Ikezu, Tadafumi C.
Li, Zonghua
Burgess, Jeremy D.
Amerna, Danilyn
O’Leary, Justin
DeTure, Michael A.
Zhao, Jing
McLean, Pamela J.
Dickson, Dennis W.
Ross, Owen A.
Bu, Guojun
Zhao, Na
author_sort Jin, Yunjung
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02421-8.
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spelling pubmed-91074502022-05-16 APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology Jin, Yunjung Li, Fuyao Sonoustoun, Berkiye Kondru, Naveen Chandra Martens, Yuka A. Qiao, Wenhui Heckman, Michael G. Ikezu, Tadafumi C. Li, Zonghua Burgess, Jeremy D. Amerna, Danilyn O’Leary, Justin DeTure, Michael A. Zhao, Jing McLean, Pamela J. Dickson, Dennis W. Ross, Owen A. Bu, Guojun Zhao, Na Acta Neuropathol Original Paper 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02421-8. Springer Berlin Heidelberg 2022-04-26 2022 /pmc/articles/PMC9107450/ /pubmed/35471463 http://dx.doi.org/10.1007/s00401-022-02421-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Jin, Yunjung
Li, Fuyao
Sonoustoun, Berkiye
Kondru, Naveen Chandra
Martens, Yuka A.
Qiao, Wenhui
Heckman, Michael G.
Ikezu, Tadafumi C.
Li, Zonghua
Burgess, Jeremy D.
Amerna, Danilyn
O’Leary, Justin
DeTure, Michael A.
Zhao, Jing
McLean, Pamela J.
Dickson, Dennis W.
Ross, Owen A.
Bu, Guojun
Zhao, Na
APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title_full APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title_fullStr APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title_full_unstemmed APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title_short APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology
title_sort apoe4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in alzheimer’s disease with lewy body pathology
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107450/
https://www.ncbi.nlm.nih.gov/pubmed/35471463
http://dx.doi.org/10.1007/s00401-022-02421-8
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