Adolescent Alcohol in 5xFAD Mouse Model Accelerates Neuroinflammation and Alzheimer's Disease Pathology Across Aging

5xFAD 小鼠模型中的青少年酒精会加速衰老过程中的神经炎症和阿尔茨海默病病理学

• 批准号: 10264162
• 负责人: Ryan Peter Vetreno
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/10264162
• 关键词: Acceleration; Acetylcholine; Adolescence; Adolescent; Adult; Age; Aging; Agonist; Alcohols; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Anti-Inflammatory Agents; Autopsy; Brain; Cholinesterase Inhibitors; Chronic; Cognition; Cognitive deficits; Data; Dementia; Development; Electrophysiology (science); Ethanol; Etiology; FPS-FES Oncogene; Female; Fiber; Functional disorder; Genes; Genetic; Genetic Diseases; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Intervention; Laboratories; Life; Link; Male Adolescents; Mus; Nerve Degeneration; Neuroimmune; Pathology; Photometry; Prevention; Proto-Oncogene Proteins c-abl; Receptor Inhibition; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Sampling; Signal Transduction; Slice; Source; Tauopathies; Testing; Therapeutic; Western Blotting; abeta accumulation; adolescent alcohol abuse; adolescent binge drinking; age related neurodegeneration; aging brain; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cognitive function; dentate gyrus; drinking onset; in vivo; innovation; male; mouse model; neurogenesis; neuroinflammation; neuron loss; neuropathology; new therapeutic target; novel; novel therapeutics; optogenetics; prevent; progressive neurodegeneration; receptor for advanced glycation endproducts; response; transmission process

ABSTRACT. Adolescent Alcohol in 5xFAD Mouse Model Accelerates Neuroinflammation and Alzheimer’s Disease Pathology Across Aging. Our laboratory and others find adolescent intermittent ethanol (AIE; 2-days EtOH/2-days NO EtOH during adolescence) primes and accelerates adult Alzheimer’s disease (AD)-related degeneration and cognitive deficits that persist in the absence of continued adult EtOH exposure. Our premise for this proposal is built on priming of common mechanisms of pathology, including chronic neuroinflammation and loss of basal forebrain cholinergic neurons (BFCNs). This proposal will test the overarching hypothesis that AIE-induced persistent, life-long loss of BFCNs and chronic neuroinflammation contribute to the onset and progression of AD-associated neuropathology and cognitive decline across aging. This hypothesis is built on our preliminary findings, including (1) AIE increase of receptor for advanced glycation end-products (RAGE) and other neuroinflammatory molecules, induction of AD-associated genes, and reductions of BFCNs, hippocampal neurogenesis, and cognitive function in adulthood; (2) increased RAGE-neuroinflammation and AD-like pathology in post-mortem human AUD brain samples of individuals with an adolescent age of drinking onset. We recently discovered that AIE accelerates adult BFCN neurodegeneration, neuroinflammation, and accumulation of amyloid-β (Aβ) in a genetic mouse model of AD. We developed an innovative mouse model using the 5xFAD genetic mouse model of AD, which recapitulates the dual Aβ accumulation and neurodegeneration observed in human AD, crossbred with ChAT- Cre mice to investigate interactions of AIE with Aβ accumulation across aging on BFCN and hippocampal pathology. Aim 1 tests the hypothesis that AIE accelerates AD-associated neuropathology in the aging brain of ChAT-Cre::5xFAD mice. We expect AIE will accelerate neuroinflammation, neurodegeneration, and AD-associated pathology across ages. Aim 2 tests the hypothesis that AIE-induced basal forebrain RAGE- neuroinflammatory signaling causes BFCN loss, neuroimmune signaling, AD pathology, and cholinergic dysfunction in the aging brain of ChAT-Cre::5xFAD mice. AIE induces RAGE-neuroinflammatory signaling and loss of BFCNs that persists into adulthood. We expect RAGE-neuroinflammatory signaling contributes to AD-associated BFCN pathology. Aim 3 tests the hypothesis that chronic activation of basal forebrain cholinergic activity during AIE prevents loss of hippocampal activity, neurogenesis, and cognitive function, and reduces AD-associated neuropathology in the aging brain of ChAT-Cre::5xFAD mice. AIE increases hippocampal neuroinflammation, reduces neurogenesis, and impairs cognition in adulthood that is prevented by anti-cholinesterase drugs. We expect BFCN activation to both identify cholinergic involvement and recover AD-associated hippocampal pathology. The proposed studies will link early life insults (i.e., adolescent binge drinking) to AD-like neurodegeneration and dementia in the aging brain, and identify potential therapeutics.

抽象的。 5xfad小鼠模型中的青少年酒精会加速神经炎症和 阿尔茨海默氏病跨衰老的病理。我们的实验室和其他人发现青少年间歇性乙醇 （aie; 2天ETOH/2天在青少年期间NO ETOH）素数并加速成年阿尔茨海默氏病 （AD）相关的变性和认知定义了在没有持续成人EtOH暴露的情况下持续存在的。 我们针对该提案的前提是建立在病理学常见机制的基础上，包括慢性 神经炎症和基本前脑胆碱能神经元（BFCN）的丧失。该建议将测试 总体假设，即AIE引起的持续性，终身丧失BFCN和慢性 神经炎症有助于与广告相关的神经病理学的发作和进展 衰老的认知能力下降。该假设建立在我们的初步发现上，包括（1）AIE增加 晚期糖基化终产物（RAGE）和其他神经炎性分子的受体的诱导 与BFCN，海马神经发生和认知功能的降低，与AD相关的基因以及降低 成年（2）增加尸体后人脑大脑中的愤怒 - 神经炎症和类似广告状的病理 青少年饮酒年龄的个体样本。我们最近发现AIE加速了 成年BFCN神经退行性，神经炎症和淀粉样蛋白β（Aβ）在遗传小鼠中的积累 AD模型。我们使用AD的5XFAD遗传小鼠模型开发了一种创新的小鼠模型，该模型 概括了在人AD中观察到的双重Aβ积累和神经退行性的，与聊天杂交 CRE小鼠研究AIE与Aβ在BFCN和海马的衰老之间的相互作用 病理。 AIM 1检验了AIE在衰老中加速AD相关神经病理的假设 Chat-Cre的大脑:: 5xfad小鼠。我们预计AIE将加速神经炎症，神经变性和 跨年龄段的广告相关病理。 AIM 2检验了AIE引起的基本前脑愤怒的假设 - 神经炎症信号传导导致BFCN丧失，神经免疫信号传导，AD病理和胆碱能 Chat-Cre衰老大脑的功能障碍:: 5XFAD小鼠。 AIE引起狂暴的神经炎症信号传导 以及持续成年的BFCN的丧失。我们预计愤怒的神经炎症信号传导有助于 与广告相关的BFCN病理学。 AIM 3检验了基本前脑长期激活的假设 AIE期间的胆碱能活性可防止海马活性，神经发生和认知的丧失 功能，并减少Chat-Cre衰老大脑:: 5XFAD小鼠的衰老大脑中与广告相关的神经病理学。 aie 增加海马神经炎症，减少神经发生，并损害成年后的认知 抗胆碱酯酶药物预防。我们预计BFCN激活既可以识别胆碱能的参与，又 恢复与广告相关的海马病理学。拟议的研究将与早期侮辱联系起来（即青少年 暴饮暴食）在衰老的大脑中为AD样神经退行性变性和痴呆症，并鉴定潜在的疗法。