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

酒精相关阿尔茨海默氏病溶酶体生物发生和自噬受损的机制

• 批准号: 10266178
• 负责人: Wen-Xing Ding
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266178
• 关键词: Affect; Age; Aging; Agonist; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Pancreatitis; Alcohols; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Amyloid beta-Protein; Autophagocytosis; Autophagosome; Biogenesis; Biology; Brain; Brain Injuries; Data; Degradation Pathway; Dementia; Development; Diet; Digestion; Elderly; Event; FRAP1 gene; Functional disorder; Gene Expression; Genetic; Heart; Hippocampus (Brain); Histopathology; Homeostasis; Human; Impaired cognition; Impairment; Knock-in; Knockout Mice; Link; Liver; Lysosomes; Mediating; Memory; Memory Loss; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Monitor; Mus; Muscle; Neurons; Nuclear; Organelles; Outcome; PPAR gamma; Pancreas; Pathology; Pharmacology; Phosphorylation; Process; Proteins; Raptors; Recovery; Risk Factors; Role; Series; Stains; Tauopathies; Testing; Transcriptional Activation; Transgenic Mice; Tuberous Sclerosis; Work; age related; aged; aging brain; aging population; base; chronic alcohol ingestion; drug candidate; drug development; experimental study; feeding; gain of function; high throughput screening; improved; liver injury; misfolded protein; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; overexpression; preservation; prevent; protein aggregation; proteostasis; tau Proteins; tau aggregation; tau-1; therapeutic target; transcription factor

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.

抽象的 酒精滥用会损害肝脏，胰腺，心脏，大脑和肌肉。酒精滥用的一个严重结果是 尽管酒精在促进阿尔茨海默氏病（AD）中的作用是 怀疑，基本机制对此知之甚少。 AD中提出的一种潜在机制是 自噬受损或不足，一种进化的溶酶体降解途径，调节 细胞器和蛋白质稳态。自噬通常随着年龄的增长而下降，导致积累 包括tau和β淀粉样蛋白以及线粒体受损的蛋白质错误折叠的蛋白质。我们最近的工作有 证明酒精会引起转录因子EB（TFEB）的功能障碍， 溶酶体生物发生。 TFEB受损导致溶酶体生物发生和线粒体恶化，导致 酒精性肝炎和胰腺炎。除了进行自噬外，我们还证明了TFEB 通过上调过氧化物体激活受体伽玛来增加线粒体生物发生 共激活因子1-α（PGC1-α）。更重要的是，改善的核TFEB水平与人类有关 尚未研究酒精性肝炎和胰腺炎，但其在与酒精相关的AD中的作用尚未进行研究。我们的 初步结果表明，酒精降低了总核TFEB，但泛素化蛋白增加 在小鼠海马中。此外，老年小鼠（22个月大）也有改善的核TFEB染色，但 与年轻小鼠相比，海马中的p62和磷酸化的tau增加（3个月大）。这些 集体观察表明，饮酒和衰老可能会协同互动以扰动 TFEB溶质体生物发生轴，从而导致脑自噬受损。在这里，我们假设慢性 饮酒化合物与年龄相关的TFEB介导的溶酶体生物发生在大脑中， 这反过来导致线粒体和蛋白质聚集体的积累。这些现象 发生在AD中，我们提出的实验有望建立脑老化，酒精之间的联系 消费和广告病理学。我们进一步预测TFEB和TFEB敲击蛋白转基因的过表达 小鼠将预防这些大脑衰老和酒精诱导的病理。我们还建议评估 从高通量筛查中鉴定出的新型TFEB激动剂的潜在神经保护作用 最近完成。拟议工作的成功完成将提供新的范式 发现TFEB在自噬和溶酶体生物学中的作用在与酒精相关的AD和脑衰老中。