Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal (“phagy”) functions, heightens the neuron’s vulnerability to genetic and environmental factors underlying Alzheimer’s disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy–lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an “inside-out” origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest “intraneuronal” stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.

自噬是降解受损或过时成分的主要溶酶体途径，通过消除有毒细胞器和肽、恢复营养和能量稳态以及抑制细胞凋亡来保护神经元。这些功能对于神经元尤其重要，神经元处于有丝分裂后状态，必须存活数十年，同时面临细胞衰老带来的日益严峻的挑战。自噬失败，尤其是与溶酶体（“吞噬”）功能下降相关的自噬失败，增加了神经元对阿尔茨海默病（AD）和其他晚发性神经退行性疾病的遗传和环境因素的脆弱性。整体自噬-溶酶体途径的组成部分和紧密整合的内溶酶体系统越来越多地成为这些疾病的主要目标。在 AD 中，高度脆弱的锥体神经元群中自噬诱导增强与溶酶体功能减弱之间的不平衡导致细胞内溶酶体中未降解底物的积聚，包括 APP-βCTF（溶酶体酸化抑制剂）和膜损伤性 Aβ 肽。在这些神经元中受损最严重的神经元中，β-淀粉样蛋白在神经元内以斑块状聚集物的形式积累，当这些神经元死亡时，这些聚集物会变成细胞外的老年斑，这反映了在人类 AD 大脑和 AD 小鼠模型中观察到的淀粉样蛋白斑块的“由内而外”起源。病理。在这篇综述中，作者描述了 AD 中溶酶体依赖性神经细胞死亡与独特的极端自噬病理学 (PANTHOS) 相关的重要性，这种病理学被描述为在 AD 最早的“神经元内”阶段由溶酶体膜通透性触发。 其他细胞死亡级联的效应子，特别是钙激活的钙蛋白酶和蛋白激酶，会导致溶酶体损伤，从而诱导组织蛋白酶渗漏并激活其他死亡级联。 AD 中的后续事件，例如小胶质细胞侵袭和神经炎症，会诱导进一步的细胞毒性。在主要的神经退行性疾病模型中，神经元死亡和随之而来的神经病理学基本上可以通过逆转潜在的原发性溶酶体缺陷来治愈，因此表明溶酶体衰竭和自噬功能障碍是溶酶体依赖性细胞死亡和 AD 发病机制的主要触发因素，也是有希望的治疗靶点。