Enhanced amyloid-β generation by γ-secretase complex in detergent-resistant membrane microdomains with reduced cholesterol levels
Enhanced amyloid-β generation by γ-secretase complex in detergent-resistant membrane microdomains with reduced cholesterol levels
复制标题
γ-分泌酶复合物在耐洗涤剂膜微域中增强淀粉样蛋白-β的生成，同时降低胆固醇水平
DOI：
10.1093/hmg/ddz297
复制
发表时间：
2020
影响因子：
3.5
通讯作者：
Suzuki T.
中科院分区：
文献类型：
--
作者：
Hata S;Hu A;Piao Y;Nakaya T;Taru H;Morishima-Kawashima M;Murayama S;Nishimura M;Suzuki T.
阿尔茨海默病 (AD) 的一个神经病理学标志是存在含有神经毒性 β 淀粉样蛋白 (Aβ) 物质的老年斑，这种老年斑是由 γ 分泌酶复合物等分泌酶裂解 β 淀粉样蛋白前体产生的，优先位于耐去污剂膜 (DRM) 区域，并包含 内切蛋白水解早老素、尼卡斯特林、前咽缺陷 1 和早老素增强子 2 的氨基和羧基末端片段。虽然一些家族性 AD 患者存在致病性 PSEN 突变，导致更多神经毒性 Aβ42 的产生，但 Aβ 的产生对散发性/迟发性 AD 的贡献仍不清楚。我们发现，在散发性 AD 患者的脑组织样本中，早老素 1 的羧基末端片段从 DRM 区域重新分布到去污剂可溶性膜（非 DRM）区域。与非痴呆对照受试者的 DRM 组分相比，AD 脑样本的 DRM 组分能够产生显着更多的 Aβ，并且胆固醇含量更低。我们进一步证明，降低培养细胞 DRM 区域的胆固醇含量有助于 γ-分泌酶成分的重新分配和 Aβ 的产生。总而言之，目前的分析表明，DRM 区域胆固醇含量降低可能通过增强 Aβ 整体生成而导致散发性/迟发性 AD。
A neuropathologic hallmark of Alzheimer’s disease (AD) is the presence of senile plaques that contain neurotoxic amyloid-β protein (Aβ) species, which are generated by the cleavage of amyloid β-protein precursor by secretases such as the γ-secretase complex, preferentially located in detergent-resistant membrane (DRM) regions and comprising endoproteolysed amino- and carboxy-terminal fragments of presenilin, nicastrin, anterior pharynx defective 1 and presenilin enhancer 2. Whereas some of familial AD patients harbor causativePSENmutations that lead to more generation of neurotoxic Aβ42, the contribution of Aβ generation to sporadic/late-onset AD remains unclear. We found that the carboxy-terminal fragment of presenilin 1 was redistributed from DRM regions to detergent-soluble membrane (non-DRM) regions in brain tissue samples from individuals with sporadic AD. DRM fractions from AD brain sample had the ability to generate significantly more Aβ and had a lower cholesterol content than DRM fractions from non-demented control subjects. We further demonstrated that lowering the cholesterol content of DRM regions from cultured cells contributed to the redistribution of γ-secretase components and Aβ production. Taken together, the present analyses suggest that the lowered cholesterol content in DRM regions may be a cause of sporadic/late-onset AD by enhancing overall Aβ generation.