Department of Neurobiology, Tel-Aviv University, 69978, Ramat-Aviv, Israel.
Mol Neurobiol. 2018 Aug;55(8):6863-6880. doi: 10.1007/s12035-018-0892-4. Epub 2018 Jan 20.
Since its discovery as a genetic risk factor for Alzheimer's disease, the APOE4 allele has been linked to the majority of the pathological findings associated with the disease progression. These include abnormalities of the endocytic, autophagic, and lysosomal machineries, which begin at the most early stages of Alzheimer's disease development. Considering that these three vesicular systems share common features and, in fact, comprise an interconnected cargo-trafficking and degradation network, some of the effects of APOE4 are interrelated, while others are system-specific. In turn, APOE4-driven impairments of endocytosis, autophagy, and lysosomal activity influence various aspects of Alzheimer's disease pathology, ranging from Aβ generation and clearance to neuronal loss and cognitive deficits. This review discusses the detrimental effects of APOE4 on the endocytic-autophagic-lysosomal axis in the context of Alzheimer's disease, as well as the various mechanisms underlying them.
自被发现是阿尔茨海默病的遗传风险因素以来，APOE4 等位基因与大多数与疾病进展相关的病理发现有关。这些发现包括内吞作用、自噬和溶酶体机制的异常，这些异常始于阿尔茨海默病发展的最早阶段。鉴于这三个囊泡系统具有共同的特征，并且实际上构成了一个相互连接的货物运输和降解网络，APOE4 的一些影响是相互关联的，而另一些则是特定于系统的。反过来，APOE4 驱动的内吞作用、自噬和溶酶体活性的损伤会影响阿尔茨海默病病理学的各个方面，从 Aβ 的产生和清除到神经元的丢失和认知缺陷。本文讨论了 APOE4 在阿尔茨海默病背景下对内吞-自噬-溶酶体轴的有害影响，以及它们背后的各种机制。
