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.

中文翻译：

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APOE4 会加剧 α-突触核蛋白的播种活性，并导致具有路易体病理学的阿尔茨海默病的神经毒性。

大约一半的阿尔茨海默病 (AD) 大脑在尸检时伴有路易病理学，这表明 α-突触核蛋白 (α-SYN) 聚集是 AD 发病机制中的调节事件。全基因组关联研究表明，载脂蛋白E（APOE4）基因的ε4等位基因是AD最强的遗传风险因素，也是路易体痴呆（LBD）重复最多的遗传风险因素，表明APOE4在淀粉样蛋白-β (Aβ) 和 α-SYN 的发病机制。APOE4 如何调节 AD 中的 α-SYN 聚集尚不清楚。在这项研究中，我们旨在确定 α-SYN 如何与 AD 相关的病理学相关，以及 APOE4 如何影响 α-SYN 播种和毒性。我们测量了尸检证实的 AD 患者 (N = 469) 脑样本中的 α-SYN 水平及其与其他已确定的 AD 相关标志物的关联，其中 54% 伴有 LB 病理学（AD + LB）。我们发现 α-SYN 水平与 Aβ40、Aβ42、tau 和 APOE 水平之间存在显着相关性，特别是在 AD + LB 的不溶性部分中。使用实时地震诱导转化 (RT-QuIC) 测定，我们测量了可溶性 α-SYN 的播种活性，发现在 AD 队列以及一小群尸检中，APOE4 加剧了 α-SYN 播种-确认具有最小阿尔茨海默型病理学的LBD大脑。我们通过在快速蛋白质液相色谱 (FPLC) 上运行的尺寸排阻色谱 (SEC) 进一步分离可溶性 AD 脑裂解物，并确定了显示最强播种活性的 α-SYN 物种 (~ 96 kDa)。最后，使用人类诱导多能干细胞 (iPSC) 衍生的神经元，我们发现，来自 APOE4 患者的 AD + LB 脑的扩增的 α-SYN 聚集体对神经元具有高毒性，而相同数量的 α-SYN 单体没有毒性。我们的研究结果表明，LB 病理学的存在与 AD 相关的病理学相关，并且 APOE4 加剧了 α-SYN 播种活性和神经毒性，为 APOE4 如何影响 AD 中的 α-SYN 发病机制提供了机制见解。