APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
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DOI：
10.1007/s00401-022-02421-8
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发表时间：
2022-06
影响因子：
12.7
通讯作者：
中科院分区：
文献类型：
--
作者：
尸检时，大约一半的阿尔茨海默病 (AD) 大脑伴有路易病理学，表明 α-突触核蛋白 (α-SYN) 聚集是 AD 发病机制中的一个受调控事件。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) 复制最多的遗传风险因素，表明 APOE4 在淀粉样蛋白-β (Aβ) 和 α-SYN 发病机制中发挥重要作用。 APOE4 如何调节 AD 中的 α-SYN 聚集尚不清楚。在本研究中，我们旨在确定 α-SYN 如何与 AD 相关病理学相关，以及 APOE4 如何影响 α-SYN 播种和毒性。我们测量了尸检确诊的 AD 患者脑样本中的 α-SYN 水平及其与其他已建立的 AD 相关标志物的关联 (N = 469)，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 的不溶性级分中。使用实时震动诱导转化 (RT-QuIC) 测定，我们测量了可溶性 α-SYN 的播种活性，发现 AD 队列中的 APOE4 加剧了 α-SYN 播种，以及一小群尸检确认的具有最小阿尔茨海默型病理的 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) 进一步分级可溶性 AD 脑裂解物，并鉴定出表现出最强接种活性的 α-SYN 物种 (~ 96 kDa)。最后，利用人诱导多能干细胞（iPSC）来源的神经元，我们发现APOE4患者AD + LB脑中扩增的α-SYN聚集体对神经元具有剧毒，而等量的α-SYN单体则没有毒性。我们的研究结果表明，LB 病理学的存在与 AD 相关病理学相关，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。在线版本包含可在 10.1007/s00401-022-02421-8 获取的补充材料。
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. The online version contains supplementary material available at 10.1007/s00401-022-02421-8.
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影响因子：
3.5
作者：
Bras J;Guerreiro R;Darwent L;Parkkinen L;Ansorge O;Escott-Price V;Hernandez DG;Nalls MA;Clark LN;Honig LS;Marder K;Van Der Flier WM;Lemstra A;Scheltens P;Rogaeva E;St George-Hyslop P;Londos E;Zetterberg H;Ortega-Cubero S;Pastor P;Ferman TJ;Graff-Radford NR;Ross OA;Barber I;Braae A;Brown K;Morgan K;Maetzler W;Berg D;Troakes C;Al-Sarraj S;Lashley T;Compta Y;Revesz T;Lees A;Cairns N;Halliday GM;Mann D;Pickering-Brown S;Dickson DW;Singleton A;Hardy J
通讯作者：
Hardy J
DOI：
10.1186/alzrt274
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Donaghy PC;McKeith IG
通讯作者：
McKeith IG
影响因子：
1.2
作者：
Furman, Jennifer L.;Holmes, Brandon B.;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
帕金森氏病的遗传结构。
DOI：
10.1016/s1474-4422(19)30287-x
发表时间：
2020-02
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Blauwendraat C;Nalls MA;Singleton AB
通讯作者：
Singleton AB
影响因子：
7.1
作者：
Groveman BR;Orrù CD;Hughson AG;Raymond LD;Zanusso G;Ghetti B;Campbell KJ;Safar J;Galasko D;Caughey B
通讯作者：
Caughey B