Microglia Activation and TLR-induced Neurodegeneration by Alcohol Promotes Progression of Alzheimer Pathology

酒精引起的小胶质细胞激活和 TLR 诱导的神经变性促进阿尔茨海默病病理学的进展

基本信息

批准号：
10625518
负责人：
FULTON T CREWS
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-09-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625518
关键词：
3xTg-AD mouse Age Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Apoptotic Autopsy Brain Brain Diseases Brain region CASP3 gene Cell Death Chronic Complement 1q Dementia Disease Ethanol Genes Genetic Genotype Goals HMGB1 gene Hippocampus Human Impaired cognition Impairment In Situ Nick-End Labeling Individual Induction of Apoptosis Inflammation Inflammatory Life Ligands Link Measurement Mediating Mediator Memory impairment MicroRNAs Microglia Modeling Molecular Profiling Mus Nerve Degeneration Neuroimmune Neurons Nuclear RNA Pathologic Pathology Phagocytes Phagocytosis Phenotype Phosphorylation Population Prefrontal Cortex Proteins Receptor Activation Rest Reverse Transcriptase Polymerase Chain Reaction Senile Plaques Signal Transduction Slice Stains Synapses TLR4 gene TLR7 gene TNFRSF10A gene TNFRSF10B gene Testing Therapeutic Toll-like receptors Tumor Necrosis Factor Receptor Up-Regulation Western Blotting abeta deposition age related alcohol effect alcohol use disorder cytokine early alcohol use fluoro jade gene induction genome wide association study glial activation in vivo innovation locomotor deficit molecular pathology molecular phenotype mouse model neuron loss neurotoxic receptor single nucleus RNA-sequencing synaptic pruning tau Proteins tau aggregation tau-1 transcriptome sequencing

项目摘要

Abstract Chronic heavy or binge alcohol use is associated with dementia and increased risk for Alzheimer's disease (AD), though mechanisms connecting the disease pathologies have not been identified. AD pathology follows a temporal progression of proinflammatory signaling in brain with Aβ deposition, tau fibril formation, synapse loss, neurodegeneration, and cognitive decline. We find increased AD pathology proteins Aβ1-42 and phosphorylated (p)-tau-181 in human alcohol use disorder (AUD) brain and after chronic binge ethanol during early life in the 3x- Tg-AD mouse model. Toll-like Receptor (TLR) proinflammatory signaling is thought to precede gross pathology in AD, and is a prominent feature of AUD. We find AUD in young individuals is associated with AD protein accumulation, and chronic binge ethanol treatment in 3x-Tg-AD mice causes persistent upregulation of proinflammatory genes that correlated strongly with levels of neurotoxic Aβ1-42 and p-tau-181 protein. Thus, we hypothesize ethanol promotes AD neurotoxic protein pathology by enhancing proinflammatory signaling. Microglia have emerged as mediators of AD pathology, contributing to Aβ plaque formation, tau propagation, synapse loss and possibly neurodegeneration. Microglial change phenotype (e.g. resting, phagocytic, proinflammatory, pruning, or neurotoxic) and microglial activation is thought to precede and promote AD pathology. Human GWAS as well as human and AD mouse single nuclei RNA sequencing (snRNA-seq) have identified AD microglia as altered, having increased C1q (pro-synaptic pruning) and reduced resting state markers (e.g. Tmem119). In human AUD brain, we find reduced resting state microglia (reduced Tmem119) with proinflammatory microglia. Further, we find chronic binge ethanol in vivo persistently increases C1q and proinflammatory cytokines mirroring AD. Thus, we hypothesize proinflammatory microglial activation by chronic heavy/binge ethanol promotes AD Aβ and tau pathology, synapse loss and neurodegeneration. This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 3x-Tg-AD mouse model (Aim 2) that features progressive Aβ and tau pathology. Apoptotic neuronal cell death is a feature of AD pathology thought to contribute to irreversible cognitive decline. We find binge ethanol increases neurodegeneration in brain regions known to have neuronal loss in AD such as prefrontal cortex (PFC) and hippocampus. Our studies implicate proinflammatory Toll-like Receptor (TLR) activation and microglial to neuronal interactions that lead to apoptotic neuronal cell death. We find chronic binge ethanol increases HMGB1-TLR4 signaling to activate microglia. Proinflammatory microglia secrete the miRNA let-7b that we found activates TLR7 in neurons. Let-7b-TLR7 signaling in neurons induces apoptotic neuronal cell death via the TNF-receptor superfamily apoptosis-inducing ligand (TRAIL). TLR4, HMGB1, let-7 and TRAIL have each been implicated in AD pathology. However, a link in AD neurodegeneration has not been identified. We hypothesize chronic binge ethanol promotes AD neurodegeneration by enhancing TRAIL- mediated apoptotic neuronal cell death. This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 5xFAD AD mouse model (Aim 3) that features Aβ-induced apoptotic neuronal death.

抽象的慢性大量或暴饮暴食与痴呆症和阿尔茨海默氏病（AD）的风险增加有关尽管尚未确定连接疾病病理的机制。广告病理遵循 Aβ沉积，tau原纤维形成，突触丧失，临时促炎信号传导的暂时进展神经变性和认知能力下降。我们发现AD病理蛋白Aβ1-42增加并磷酸化增加（P）-tau-181在人类酒精饮酒障碍（AUD）大脑以及早期生命中慢性暴饮暴食之后 TG-AD鼠标模型。 Toll样受体（TLR）促炎信号传导被认为是在总病理学之前在AD中，是AUD的重要特征。我们发现年轻人的AUD与AD蛋白有关 3x-TG-AD小鼠的累积和慢性暴饮暴食治疗导致持续更新与神经毒性Aβ1-42和P-TAU-181蛋白水平密切相关的促炎基因。所以，我们假设乙醇通过增强促炎信号传导来促进AD神经毒性蛋白质病理。小胶质细胞已成为AD病理学的介体，有助于Aβ斑块形成，tau繁殖，突触丧失和可能的神经变性。小胶质变化表型（例如静止，吞噬细胞，促炎，修剪或神经毒性）和小胶质细胞激活被认为是在AD之前的病理。人类GWAS以及人类和AD小鼠单核RNA测序（SNRNA-SEQ）具有将AD小胶质细胞识别为改变，增加了C1Q（促肌修剪）并降低静息状态标记（例如TMEM119）。在人类的大脑中，我们发现静息状态小胶质细胞减少（TMEM119降低）促炎小胶质细胞。此外，我们发现体内慢性狂饮乙醇持续增加了C1q，并且促炎细胞因子镜像AD。这，我们通过慢性重/暴饮暴食乙醇促进ADAβ和TAU病理，突触丧失和神经退行性。该假设将在人类AD后大脑（AIM 1）和3x-TG-AD小鼠模型中进行检验（AIM 2）这具有渐进的Aβ和TAU病理。凋亡神经元细胞死亡是AD病理学的一个特征，认为导致不可逆的认知能力下降。我们发现狂饮乙醇会增加已知在AD中具有神经元丧失的脑区域的神经变性。前额叶皮层（PFC）和海马。我们的研究暗示促炎性收费受体（TLR）激活和小胶质细胞与导致凋亡神经元细胞死亡的神经元相互作用。我们发现慢性暴饮暴食乙醇增加了HMGB1-TLR4信号传导以激活小胶质细胞。促炎小胶质细胞分泌我们发现的miRNA let-7b激活了神经元中的TLR7。神经元中的let-7b-tlr7信号传导诱导凋亡神经元细胞死亡通过TNF受体超家族凋亡诱导的配体（TRAIL）。 TLR4，HMGB1，Let-7 在AD病理学中，每个人都隐含了轨迹。但是，AD神经退行性中的链接尚未确定。我们假设慢性暴饮暴食乙醇通过增强踪迹来促进AD神经退行性。介导的凋亡神经元细胞死亡。该假设将在人类广告后大脑中进行检验（目的 1）以及具有Aβ诱导的凋亡神经元死亡的5XFAD AD小鼠模型（AIM 3）。