4.6 Article

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

期刊

ACTA NEUROPATHOLOGICA
卷 143, 期 6, 页码 641-662

出版社

SPRINGER
DOI: 10.1007/s00401-022-02421-8

关键词

Alzheimer's disease; Lewy body dementia; Apolipoprotein E; alpha-synuclein; Seeding; RT-QuIC

资金

  1. Mayo Alzheimer's Disease Research Center Developmental Grant
  2. NIH [U19AG069701]
  3. Mayo Clinic Functional Genomics of Lewy body disease Program - Little Family Foundation
  4. Mayo Clinic Center of Individualized Medicine
  5. MSA Coalition award
  6. Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic

向作者/读者索取更多资源

Approximately half of AD patients have concomitant Lewy pathology, and the APOE4 gene plays an important role in the pathogenesis of both Aβ and α-SYN. APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD.
Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that alpha-synuclein (alpha-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the epsilon 4 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-beta (A beta) and alpha-SYN pathogenesis. How APOE4 modulates alpha-SYN aggregation in AD is unclear. In this study, we aimed to determine how alpha-SYN is associated with AD-related pathology and how APOE4 impacts alpha-SYN seeding and toxicity. We measured alpha-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 alpha-SYN and those of A beta 40, A beta 42, 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 alpha-SYN and found that alpha-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 alpha-SYN species (similar to 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified alpha-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of alpha-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates alpha-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects alpha-SYN pathogenesis in AD.

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