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

抽象的。青少年酒精在5xFAD小鼠模型中加速神经炎症和 老年阿尔茨海默病病理学。我们的实验室和其他人发现青少年间歇性酒精 (AIE；2天无酒精/2天无酒精青春期)引发并加速成人阿尔茨海默病 (Ad)在成人没有持续接触乙醇的情况下，持续存在的与退化和认知缺陷有关的疾病。 我们这个提议的前提是建立在共同的病理机制的基础上，包括慢性 神经炎症和基底前脑胆碱能神经元(BFCNs)的丢失。这项提案将考验 最重要的假设是，AIE导致BFCNs和慢性 神经炎症在AD相关神经病理的发生和发展中起作用 随着年龄的增长，认知能力会下降。这一假设建立在我们的初步发现基础上，包括(1)AIE增加 晚期糖基化终产物受体(RAGE)和其他神经炎性分子的诱导 AD相关基因、BFCNs减少、海马神经发生和认知功能 成人；(2)死后人AUD脑中RAGE-神经炎症和AD样病理增加 青春期开始饮酒的个体样本。我们最近发现，AIE加速了 遗传性小鼠的成体BFCN神经变性、神经炎症和淀粉样蛋白β(Aβ)积聚 AD的模型。我们利用AD的5xFAD遗传小鼠模型开发了一种创新的小鼠模型，该模型 概述了在与ChAT-1杂交的人类AD中观察到的双Aβ积聚和神经变性。 Cre小鼠研究AIE与增龄性脑脊束核和海马区Aβ蓄积的相互作用 病理学。目的1验证AIE在衰老过程中加速AD相关神经病理的假说 Chat-Cre：：5xFAD小鼠脑。我们预计AIE会加速神经炎症、神经变性和 不同年龄段的AD相关病理。目的2验证AIE诱导的基底前脑激怒- 神经炎性信号导致BFCN丢失、神经免疫信号、AD病理和胆碱能 Chat-Cre：：5xFAD小鼠衰老脑功能障碍。AIE诱导RAGE-神经炎症信号转导 以及持续到成年期的BFCNs丢失。我们预计RAGE-神经炎性信号有助于 AD相关的BFCN病理。AIM 3验证了基底前脑慢性激活的假说 AIE期间胆碱能活动可防止海马区活动、神经发生和认知功能的丧失 功能，并减少Chat-Cre：：5xFAD小鼠衰老大脑中与AD相关的神经病理。AIE 增加海马神经炎症，减少神经发生，并在成年后损害认知，即 可通过抗胆碱酯酶药物预防。我们期望BFCN的激活既能识别胆碱能参与，又能识别 恢复AD相关的海马区病理。拟议的研究将把早年的侮辱(即青少年)联系起来 大量饮酒)到衰老大脑中的AD样神经变性和痴呆症，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.