Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease

摘要 酗酒会损害肝脏、胰腺、心脏、大脑和肌肉。酗酒的一个严重后果是 认知障碍和痴呆症。尽管酒精在促进阿尔茨海默病(AD)中的作用是 人们怀疑，根本的机制还不太清楚。AD中提出的一种潜在机制是 自噬受损或不足，这是一种进化上保守的溶酶体降解途径，调节 细胞器和蛋白质动态平衡。自噬一般会随着年龄的增长而下降，结果是积累了 错误折叠的蛋白质，包括tau和β淀粉样蛋白，以及受损的线粒体。我们最近的工作是 证明酒精诱导转录因子EB(TFEB)的功能障碍，TFEB是一种主要的调控因子 溶酶体的生物发生。TFEB受损导致溶酶体生物合成和有丝分裂能力下降，从而导致 酒精性肝炎和胰腺炎。除了调节自噬，我们还证明了TFEB 上调过氧化物酶体增殖物激活受体γ促进线粒体生物发生 辅活化子1-α(pGc1-α)。更重要的是，核TFEB水平下降与人类 酒精性肝炎和胰腺炎，但其在酒精相关性AD中的作用尚未被调查。我们的 初步结果显示，酒精降低了总TFEB和核TFEB，但增加了泛素化的蛋白质 在小鼠海马区。此外，老龄小鼠(22月龄)也有核TFEB染色减少，但 与3个月大的幼鼠相比，海马区p62和磷酸化的Tau增加。这些 集体观察表明，饮酒和衰老可能会协同作用，扰乱 TFEB-溶酶体生物发生轴，从而导致脑部自噬受损。在这里，我们假设慢性 饮酒会导致TFEB介导的脑内溶酶体生物发生的年龄相关性降低， 这反过来又会导致受损的线粒体和蛋白质聚集体的积累。这些现象 发生在阿尔茨海默病中，我们提出的实验承诺在大脑老化、酒精和 消费和AD病理。我们进一步预测了TFEB和TFEB敲打蛋白转基因的过表达 小鼠将保护大脑免受这些老化和酒精引起的病理影响。我们还建议评估 从高通量筛选中鉴定的新型TFEB激动剂的潜在神经保护作用 最近完工了。拟议工作的成功完成将提供一个新的范例 揭示TFEB在酒精相关AD和脑老化的自噬和溶酶体生物学中的作用。

Abstract Alcohol abuse damages liver, pancreas, heart, brain, and muscle. One severe outcome of alcohol abuse is cognitive impairment and dementia. Although a role for alcohol in promoting Alzheimer's disease (AD) is suspected, the underlying mechanisms are poorly understood. One proposed underlying mechanism in AD is impaired or insufficient autophagy, an evolutionarily conserved lysosomal degradation pathway that regulates organelle and protein homeostasis. Autophagy generally declines with age, resulting in an accumulation of misfolded proteins including tau and β amyloid, as well as damaged mitochondria. Our recent work has demonstrated that alcohol induces dysfunction of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Impaired TFEB leads to decreased lysosomal biogenesis and mitophagy resulting in alcoholic hepatitis and pancreatitis. In addition to regulating autophagy, we also demonstrated that TFEB increased mitochondrial biogenesis by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). More importantly, decreased nuclear TFEB levels is associated with human alcoholic hepatitis and pancreatitis but its role in alcohol-associated AD has not been investigated. Our preliminary results showed that alcohol decreased total and nuclear TFEB but increased ubiquitinated proteins in mouse hippocampi. In addition, aged mice (22-months old) also have decreased nuclear TFEB staining but increased p62 and phosphorylated Tau in the hippocampi compared with young mice (3-months old). These collective observations suggest that alcohol consumption and aging may synergistically interact to perturb the TFEB-lysosome biogenesis axis, thereby leading to impaired brain autophagy. Here, we hypothesize chronic alcohol consumption compounds age-related decrease of TFEB-mediated lysosomal biogenesis in the brain, which in turn leads to an accumulation of damaged mitochondria and protein aggregates. These phenomena occur in AD, and our proposed experiments promise to establish links between brain aging, alcohol consumption, and AD pathology. We further predict overexpression of TFEB and TFEB knockin transgenic mice will protect against these brain aging and alcohol-induced pathologies. We also propose to assess potential neuroprotective effects of novel TFEB agonists identified from a high-throughput screening that were recently completed. The successful completion of the proposed work will provide a new paradigm of uncovering the role of TFEB in autophagy and lysosome biology in alcohol-associated AD and brain aging.