Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer's disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-β clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-β and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer's disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer's disease pathology.

中文翻译：

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内溶酶体失调和迟发性阿尔茨海默病：遗传风险因素的影响。


越来越多的证据表明，降解途径中的细胞失调会导致神经退行性疾病（包括阿尔茨海默病）的发生和进展。自噬和内溶酶体稳态需要在整个生命过程中维持，因为它们是涉及有毒淀粉样肽的产生和错误折叠或聚集蛋白的清除的主要细胞机制。因此，内溶酶体和自噬通量的变化作为这些途径或区室降解活性的衡量标准，也可能直接影响疾病相关机制，例如淀粉样蛋白-β通过血脑屏障的清除和神经元间的传播。 β 淀粉样蛋白和/或 Tau 种子，影响突触功能、可塑性和代谢。晚发性阿尔茨海默病的几种遗传风险因素的出现，这些因素在功能上与内吞转运调节（包括胆固醇代谢和清除）相关，支持了这样一种观点，即自噬/溶酶体通量在衰老过程中可能变得更加脆弱，从而导致疾病发作。在这篇综述中，我们讨论了我们目前对风险基因 APOE4、BIN1、CD2AP、PICALM、PLD3 和 TREM2 的了解，以及它们根据迟发性阿尔茨海默病病理学对内溶酶体 (dys) 调节的影响。