早老蛋白1功能缺失性突变导致家族性阿尔茨海默病的研究进展

阿尔茨海默病（AD）是一种衰老相关的神经退行性疾病，主要病理特征是大脑中存在异常聚集的β淀粉样蛋白（Aβ）。AD可分为家族性和散发性，其中早老蛋白1（PS1）是家族性AD最主要的风险基因，PS1突变占已知致家族性AD突变的80%以上。PS1是构成γ-分泌酶的催化亚基，后者负责加工Aβ前体蛋白（APP）生成Aβ。虽然新型PS1突变日渐被报道，但其诱发家族性AD的分子机制仍无定论。由于90%的PS1突变降低γ-分泌酶活性，学术界提出了PS1功能缺失性突变假说，认为PS1突变通过显性负效应导致PS1功能下降或缺失是诱发家族性AD的关键。近年，大量实验研究支持了该假说。首先，PS1功能缺失性突变通过干扰γ-分泌酶在APP上的切割位点促进长链Aβ生成，进而增加Aβ₄₂/Aβ₄₀比率；其次，PS1功能缺失性突变可破坏神经细胞内质网中的钙离子稳态以及通过阻断神经细胞自噬活性导致APP加工产物的异常聚集；再者，PS1功能缺失性突变可通过干扰神经元的内吞和转胞吞作用诱发神经元萎缩以及通过激活神经免疫细胞（星形胶质细胞和小胶质细胞）增强神经炎症；最后，PS1功能缺失性突变降低糖酵解和乳酸输出，破坏机体对神经元的能量供应。本文总结了PS1功能缺失性突变诱发家族性AD的分子机制，并对今后潜在的研究方向进行了探讨。

Progress on loss-of-function hypothesis of presenilin-1 mutations in Alzheimer diseases

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and is associated with the accumulation of amyloid-β (Aβ) peptides in patient brains. AD can be classified into the familial type and sporadic type. Presenilin-1 (PS1) is the major risk gene for familial AD (fAD) because its mutations comprised over 80%of the total mutations causing fAD. PS1 is the catalytic subunit of the enzyme γ-secretase, which is responsible for the proteolytic cleavage of amyloid precursor protein (APP) to produce Aβ. Although novel fAD-causing mutations in PS1 are being reported increasingly, the molecular mechanisms underlying how these mutations induce fAD remain elusive. Since over 90%of the fAD-causing mutations in PS1 leads to a reduction of γ-secretase activity, the PS1 loss-of-function mutation hypothesis has been emerged, which suggests that the loss of PS1 functions may be the root cause of AD. Recently, increasing number of evidence supports this hypothesis. First, PS1 loss-of-function mutations increase the production of long-length Aβ by disturbing the cleavage sites of γ-secretase APP, thereby increasing the ratio of Aβ₄₂/Aβ₄₀; Second, PS1 loss-of-function mutations dysregulate endoplasmic reticulum calcium homeostasis in neurons; Third, PS1 loss-of-function mutations inhibit the autophagy activity of neurons, resulting in the abnormal accumulation of cleaved products from APP; Fourth, PS1 loss-of-function mutations alter the endocytosis and transcytosis processes in neurons, leading to neuratrophy; Fifth, PS1 loss-of-function mutations activate brain immune cells (astrocytes and microglia), which mount a strong neuroinflammation response; Last, PS1 loss-of-function mutations reduce the rates of glycolysis and the production of lactic acid, disrupting the balance of neuronal energy supply. In this article we summary the research progress on the PS1 loss-of-function hypothesis and pose several topics which would guide studies of this field in future.