lysosomal 蛋白酶介导的 APP 降解是依赖于 pH 的,对突变敏感的,并促进 tau 蛋白质分解
Caroline Ackley1, Zoe Liau1,2, Shruti Arya1
1Edward and Pearl Fein Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190 California USA.
概括
这项研究揭示了 lysosomal 酶处理粉样蛋白前体蛋白 (APP) 和其变体,将 APP 与 tau 分裂联系起来,并建议新的阿尔茨海默病 (AD) 治疗点.
科学领域:
- 神经科学是一个神经科学.
- 生物化学 生物化学
- 分子生物学分子生物学
背景情况:
- 粉样β (Aβ) 积累是阿尔茨海默病 (AD) 发病的核心原因.
- 已知由秘酶处理的粉样蛋白前体蛋白 (APP),但对 lysosomal 降解的理解较少.
- 在APP的突变可以导致早期发病的AD.
研究的目的:
- 研究 lysosomal 蛋白酶 (cathepsins) 在 APP 降解中的作用.
- 为了绘制 cathepsins.app 目标的 APP 分裂点的地图.
- 为了检查pH和病原性APP变体对裂纹的影响.
主要方法:
- 通过质谱法 (MSP-MS) 进行多重复合基质剖析,以绘制裂痕部位的地图.
- 基于细胞的和体外的测试,以研究由甲素降解APP.
主要成果:
- APP在内溶酶体区内得到丰富,并通过cathepsins进行处理.
- APP裂痕部位对pH和致病变体 (E693G,E693Q) 很敏感.
- APP (sAPP) 的可溶性域增强了在体外的tau分裂由cathepsin G (CTSG).
结论:
- 在AD中,APP的溶酶体处理至关重要.
- 确定了APP和tau裂变之间的联系.
- 这些发现表明AD和其他神经退行性疾病的新型治疗点.
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