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

基本信息

批准号：
10405008
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
项目类别：
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/10405008
关键词：
Affect Age Aging Agonist Alcohol abuse Alcohol consumption Alcoholic Hepatitis Alcoholic Pancreatitis Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos 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 brain dysfunction 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

项目摘要

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。尽管酒精在促进阿尔茨海默氏病 (AD) 方面发挥着重要作用。怀疑，AD 的潜在机制尚不清楚。自噬受损或不足，这是一种进化上保守的溶酶体降解途径，可调节细胞器和蛋白质稳态通常随着年龄的增长而下降，导致细胞的积累。我们最近的工作发现了错误折叠的蛋白质，包括 tau 蛋白和 β 淀粉样蛋白，以及受损的线粒体。酒精会导致转录因子 EB (TFEB) 功能障碍，转录因子 EB 是细胞的主要调节因子溶酶体生物发生受损导致溶酶体生物发生和线粒体自噬减少。除了调节自噬之外，我们还证明了 TFEB 在酒精性肝炎和胰腺炎中的作用。通过上调过氧化物酶体增殖物激活受体γ增加线粒体生物发生更重要的是，核 TFEB 水平降低与人类相关。酒精性肝炎和胰腺炎，但其在酒精相关 AD 中的作用尚未得到研究。初步结果表明，酒精会降低总 TFEB 和核 TFEB，但会增加泛素化蛋白此外，老年小鼠（22 个月大）的核 TFEB 染色也有所减少，但与年轻小鼠（3 个月大）相比，海马中的 p62 和磷酸化 Tau 蛋白增加。集体观察表明，饮酒和衰老可能协同相互作用，扰乱 TFEB-溶酶体生物发生轴，从而导致大脑自噬受损。饮酒年龄化合物相关的大脑中 TFEB 介导的溶酶体生物合成的减少，这反过来又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 AD 中，我们提出的实验有望在大脑衰老和酒精之间建立联系我们进一步预测 TFEB 和 TFEB 敲入转基因的过度表达。小鼠将预防这些大脑老化和酒精引起的病变。我们还建议进行评估。通过高通量筛选鉴定出新型 TFEB 激动剂的潜在神经保护作用最近完成的拟议工作的成功完成将提供一个新的范式。揭示 TFEB 在自噬和溶酶体生物学中在酒精相关 AD 和大脑衰老中的作用。