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

摘要。5xFAD小鼠模型中的青少年酒精加速神经炎症和神经毒性 老年痴呆症的病理学我们的实验室和其他人发现青少年间歇性乙醇 (AIE;青春期2天EtOH/2天NO EtOH）引发并加速成人阿尔茨海默病 （AD）相关的变性和认知缺陷，在没有持续成人EtOH暴露的情况下持续存在。 我们提出这一建议的前提是建立在启动常见的病理机制，包括慢性 神经炎症和基底前脑胆碱能神经元（BFCN）的损失。这项提案将考验 总体假设是，AIE诱导了持续的、终生的BFCN损失和慢性 神经炎症有助于AD相关神经病理学的发作和进展， 认知能力下降这一假设是建立在我们的初步研究结果，包括（1）AIE增加 晚期糖基化终末产物受体（AGEs）和其他神经炎性分子，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AUD脑中RAGE神经炎症和AD样病理学增加 青少年开始饮酒年龄的个体样本。我们最近发现， 一只遗传性小鼠的成年BFCN神经变性、神经炎症和淀粉样蛋白-β（Aβ）蓄积 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， 概括了在人类AD中观察到的双重Aβ积聚和神经变性，与ChAT杂交， Cre小鼠研究AIE与BFCN和海马中Aβ累积的相互作用 病理目的1验证AIE加速AD相关神经病理学的假设， ChAT-Cre：：5xFAD小鼠的脑。我们预计AIE将加速神经炎症，神经变性， 不同年龄段的AD相关病理学。目的2检验AIE诱导的基底前脑损伤的假设， 神经炎性信号传导导致BFCN损失、神经免疫信号传导、AD病理和胆碱能 ChAT-Cre：：5xFAD小鼠衰老大脑中的功能障碍。AIE诱导RAGE-神经炎症信号传导 以及持续到成年期的BFCN丢失。我们预计RAGE神经炎症信号传导有助于 AD相关BFCN病理学。目的3：验证基底前脑慢性激活 AIE期间的胆碱能活动可防止海马活动、神经发生和认知功能丧失 功能，并减少ChAT-Cre：：5xFAD小鼠衰老大脑中AD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能力， 通过抗胆碱酯酶药物预防。我们希望BFCN激活既能识别胆碱能参与， 恢复AD相关的海马病理学。拟议的研究将把早期生活中的侮辱（即，青少年 狂饮）到AD样神经退行性变和老年脑痴呆症，并确定潜在的治疗方法。

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.