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: 10621885
• 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/10621885
• 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; Crossbreeding; DDX6 gene; Data; Dementia; Development; Electrophysiology (science); Ethanol; Etiology; FPS-FES Oncogene; Female; Fiber; Functional disorder; Genes; Genetic; Genetic Diseases; Hippocampus; 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 alcohol exposure; adolescent binge drinking; age related neurodegeneration; aging brain; antagonist; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; cognitive function; dentate gyrus; drinking onset; glial activation; 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 老年痴呆症的病理学。我们的实验室和其他实验室发现青少年间歇性乙醇 （AIE；青春期 2 天乙醇/2 天无乙醇）引发并加速成人阿尔茨海默病 (AD) 相关的退化和认知缺陷在成人持续接触乙醇的情况下持续存在。 我们提出这一建议的前提是建立在共同病理机制的启动之上，包括慢性 神经炎症和基底前脑胆碱能神经元（BFCN）丧失。该提案将测试 总体假设是 AIE 导致 BFCN 持续终生丧失，并导致慢性 神经炎症有助于 AD 相关神经病理学的发生和进展 随着年龄的增长认知能力下降。这一假设建立在我们的初步发现之上，包括 (1) AIE 增加 晚期糖基化终末产物 (RAGE) 和其他神经炎症分子的受体，诱导 AD 相关基因以及 BFCN、海马神经发生和认知功能的减少 成年期； (2) 死后人类 AUD 大脑中 RAGE 神经炎症和 AD 样病理增加 青少年时期开始饮酒的个体样本。我们最近发现 AIE 加速 成年 BFCN 遗传小鼠神经变性、神经炎症和淀粉样蛋白-β (Aβ) 的积累 AD模型。我们利用 AD 的 5xFAD 基因小鼠模型开发了一种创新的小鼠模型，该模型 概括了在与 ChAT 杂交的人类 AD 中观察到的双重 Aβ 积累和神经变性 Cre 小鼠研究 AIE 与 BFCN 和海马衰老过程中 Aβ 积累的相互作用 病理。目标 1 检验 AIE 加速衰老过程中 AD 相关神经病理学的假设 ChAT-Cre::5xFAD 小鼠的大脑。我们预计 AIE 将加速神经炎症、神经变性和 各个年龄段的 AD 相关病理。目标 2 检验 AIE 诱导的基底前脑 RAGE- 的假设 神经炎症信号传导导致 BFCN 丢失、神经免疫信号传导、AD 病理学和胆碱能 ChAT-Cre::5xFAD 小鼠衰老大脑功能障碍。 AIE 诱导 RAGE 神经炎症信号传导 BFCN 的丧失持续到成年期。我们预计 RAGE 神经炎症信号传导有助于 AD 相关的 BFCN 病理学。目标 3 检验基底前脑慢性激活的假设 AIE 期间的胆碱能活动可防止海马活动、神经发生和认知能力的丧失 功能，并减少 ChAT-Cre::5xFAD 小鼠衰老大脑中与 AD 相关的神经病理学。人工智能工程师协会 增加海马神经炎症，减少神经发生，并损害成年期的认知 可用抗胆碱酯酶药物预防。我们期望 BFCN 激活能够识别胆碱能参与和 恢复 AD 相关的海马病理。拟议的研究将把早期生活中的侮辱（即青少年时期的侮辱）联系起来 酗酒）会导致衰老大脑中类似 AD 的神经变性和痴呆，并确定潜在的治疗方法。