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Chronic alcohol-induced mitochondrial oxidant stress and Alzheimer's related pathogenesis

慢性酒精诱导的线粒体氧化应激和阿尔茨海默病相关发病机制

基本信息

批准号：
10264166
负责人：
Steven Michael Graves
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264166
关键词：
APP-PS1 Abstinence Age Alcohol abuse Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Attenuated Axon Binding Biosensor Brain Brain Stem Cell Nucleus Chronic Clinical Data Dependence Development Disease Disease Progression Electron Transport Electrons Enzymes Fluorescent in Situ Hybridization Genetic Genetic Techniques Glutamates Heavy Drinking Hippocampus (Brain)Immunohistochemistry Impairment Knock-in Mouse Laser Scanning Microscopy Lead Lesion Measures Mediating Messenger RNA Metabolism Mitochondria Mitochondrial Matrix Monoamine Oxidase Monoamine Oxidase Inhibitors Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Norepinephrine Outcome Oxidation-Reduction Pathogenesis Pathology Patients Pharmaceutical Preparations Pharmacology Phase Phenelzine Pilot Projects Process Proteins Public Health Risk Risk Factors Role Slice Testing Transcript Vesicle Western Blotting abeta deposition alcohol abstinence beta amyloid pathology chronic alcohol ingestion drinking water druggable target experimental study genetic approach high risk inhibitor/antagonist locus ceruleus structure mild cognitive impairment monoamine mouse model neuron loss novel oxidant stress pre-clinical problem drinker two-photon vesicular monoamine transporter 2

项目摘要

PROJECT SUMMARY Alcohol is the most commonly abused substance and Alzheimer’s disease (AD) is the most common neurodegenerative disease. Alcohol abuse is a significant risk factor for the development of AD and this intersection of alcohol abuse and AD presents an enormous public health concern. Chronic, heavy alcohol use is associated with a higher risk of developing AD and accelerated progression of the disease. The clinical phase of AD is preceded by a decades long preclinical phase that is characterized by early deposition of amyloid b (Ab) and neuronal loss in the locus coeruleus (LC), a norepinephrine nucleus in the brainstem. We propose a novel mechanism by which chronic alcohol consumption renders LC neurons vulnerable to degeneration. We recently discovered a novel cellular mechanism that selectively induces mitochondrial oxidant stress in axons. Cytosolic monoamines, including norepinephrine, are metabolized by monoamine oxidase (MAO) enzymes and the electrons generated from this process are directly shuttled into the mitochondrial intermembrane space. This produces increased mitochondrial oxidant stress selectively in axons. We propose that chronic alcohol consumption activates this novel mechanism of axonal mitochondrial oxidant stress leading to a degenerative cascade in LC neurons. Our pilot studies suggest that chronic, intermittent alcohol consumption decreased VMAT2 mRNA and increased axonal oxidant stress in the LC. Importantly, we also showed that Ab pathology was increased in APP/PS1 mice that underwent chronic, intermittent alcohol consumption compared to age-matched water drinking mice. Thus, we hypothesize that chronic, intermittent alcohol consumption decreases VMAT2 expression in the LC leading to increased metabolism of cytosolic norepinephrine by MAO, which then causes axonal mitochondrial oxidant stress. This elevated mitochondrial oxidant stress would then accelerate LC degeneration and Ab deposition in mouse models of AD. We will test this hypothesis using 2 genetic mouse models of AD, APP/PS1 and APP-NL knock- in mice, which develop progressive Ab pathology. A combination of cutting-edge two-photon laser scanning microscopy (2PLSM) in ex vivo brain slices, false fluorescent neurotransmitters (FFNs), genetically encoded redox biosensors, immunohistochemistry, stereological, pharmacological, and genetic techniques will be used to investigate the effects of chronic, intermittent alcohol consumption on VMAT2 expression, VMAT2 packaging of norepinephrine, LC axonal mitochondrial oxidant stress, LC degeneration, Ab pathology, and MAO-dependence. In aim 1, we will determine the effect of chronic, intermittent alcohol consumption on LC axonal mitochondrial oxidant stress. In aim 2, we will determine the effect of chronic alcohol consumption on LC degeneration and Ab pathology. Our proposed experiments will be the first to explore a novel axonal mitochondrial oxidant stress-mediated neurodegenerative mechanism underlying the interaction between chronic alcohol consumption and AD.

项目总结