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Adolescent Alcohol Abuse, PTSD and Alzheimer's Disease Administrative Supplement

青少年酒精滥用、创伤后应激障碍和阿尔茨海默病行政补充

基本信息

批准号：
10715295
负责人：
L Judson Chandler
金额：
$ 37.75万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10715295
关键词：
APP-PS1 Acceleration Acute Address Administrative Supplement Adolescent Adult Age Months Aging Alcohol abuse Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amygdaloid structure Animal Model Anxiety Behavior Behavioral Brain Brain Pathology Brain region Cognitive deficits Complement Controlled Study Cues Dementia Development Disease Disease Progression Electrophysiology (science)Encephalitis Ethanol Exhibits Extinction Female Fright Functional disorder Future Genetic Gliosis Goals Health Hippocampus Human Immunohistochemistry Impaired cognition Inflammation Knowledge Learning Light Link Literature Longevity Maintenance Measures Medial Memory Memory impairment Mental Depression Modeling Molecular Mus Mutant Strains Mice Mutation Neuroimmune Neurons Onset of illness Pathologic Pathology Phase Physiological Positioning Attribute Post-Traumatic Stress Disorders Pre-Clinical Model Predisposition Process Rattus Reporting Research Personnel Risk Risk Factors Role Sex Differences Signal Transduction Slice Suggestion Symptoms Synapses Synaptic plasticity System Testing Time Tissues Transgenic Organisms Western Blotting adolescent alcohol abuse adolescent alcohol exposure age related alcohol exposure alcohol research alcohol use disorder axonal degeneration behavioral study brain circuitry conditioned fear design early onset entorhinal cortex epidemiology study experience experimental study granule cell improved interest locus ceruleus structure male neural circuit neuroinflammation neuronal circuitry neuronal excitability neurotransmission noradrenergic novel object recognition parent grant pharmacologic preclinical study prevent prodromal Alzheimer&apos s disease receptor sex underage drinking

项目摘要

PROJECT SUMMARY/ABSTRACT Anxiety and depression co-occur in both alcohol use disorder (AUD) and Alzheimer’s disease, and both illnesses target the noradrenergic system and circuits in hippocampus and amygdala. This overlap in symptoms and impacted brain regions raise the question of shared mechanisms, and whether adolescent intermittent ethanol exposure can set the brain on a trajectory that makes it more susceptible to Alzheimer’s pathology and related dementia in aging. Conflicting literature shows light to moderate alcohol drinking may be protective, while others report increased risk, or no effect, of alcohol use and AD risk. Variable durations and intensity of alcohol use and measures of dementia likely contribute to the lack of a coherent understanding of the interactions of alcohol exposure and development of Alzheimer’s disease. Use of preclinical models and well controlled studies will provide a platform to understand possible overlapping mechanisms that can trigger AD following significant ethanol exposure during adolescence. Surprisingly, to date, extremely few preclinical studies have investigated the interaction between alcohol use and AD risk and disease progression. In support of the hypothesis that AUD augments AD pathology, a recent study using adolescent intermittent ethanol exposure (P25-55) in 3xFAD mice harboring three human AD mutations displayed increased Aβ1–42 accumulation in hippocampus, amygdala, and entorhinal cortex and pTau accumulation in hippocampus of adult females. These mice also experienced increased anxiety and learning and memory deficits. Importantly, pharmacologically blocking inflammation prevented both the pathological and behavioral changes. In another study in humanize pTau mutant mice, intermittent ethanol increased excitability of locus coeruleus (LC) noradrenergic neurons with a greatest effect in females. Our expertise in AUD, AD, sex differences and synaptic circuits skillfully and uniquely positions us to test the overarching hypothesis that adolescent intermittent ethanol accelerates AD pathology and synaptic dysfunction and shortens the period of prodromal AD. Aim 1 will test the hypothesis that AIE exposure accelerates accumulation of Ab and pTau and increases gliosis and neuronal and synaptic dysfunction during prodromal AD in adult TgF344-AD rats. Aim 2 will test the hypothesis that AIE exposure accelerates deficits in learning and memory, increases anxiety, and impaires fear extinction during the prodromal phase of AD in adult TgF344-AD rats. These studies will provide foundational information regarding the interaction of AUD and AD and the findings will serve as a launch pad for future mechanistic studies.

项目总结/文摘