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.

抽象的长期大量饮酒或酗酒与痴呆症和阿尔茨海默氏病 (AD) 的风险增加有关，尽管 AD 病理学之间的联系机制尚未确定。 Aβ 沉积、tau 纤维形成、突触丢失等大脑进展中促炎信号传导的时间性我们发现 AD 病理蛋白 Aβ1-42 和磷酸化增加。 (p)-tau-181 在人类酒精使用障碍 (AUD) 大脑中以及在生命早期长期酗酒后的 3x- Tg-AD 小鼠模型。Toll 样受体 (TLR) 促炎症信号传导被认为先于大体病理学发生。 AD 中的 AUD 是 AUD 的一个显着特征，我们发现年轻人中的 AUD 与 AD 蛋白相关。 3x-Tg-AD 中的积累和长期暴饮乙醇治疗会导致小鼠持续上调促炎基因与神经毒性 Aβ1-42 和 p-tau-181 蛋白的水平密切相关。乙醇通过增强促炎信号传导来促进 AD 神经毒性蛋白病理学。小胶质细胞已成为 AD 病理学的介质，有助于 Aβ 斑块形成、tau 增殖、突触损失和可能的神经变性表型（例如静息、吞噬、促炎性、修剪性或神经毒性）和小胶质细胞激活被认为先于并促进 AD 人类 GWAS 以及人类和 AD 小鼠单核 RNA 测序 (snRNA-seq) 具有发现 AD 小胶质细胞发生改变，C1q（突触前修剪）增加，静息状态减少在人类 AUD 大脑中，我们发现静息态小胶质细胞减少（Tmem119 减少）。此外，我们发现体内慢性暴食乙醇会持续增加 C1q 和促炎性细胞因子反映了 AD 因此，我们通过以下方式帮助促炎性小胶质细胞的激活。长期大量/暴饮乙醇会促进 AD Aβ 和 tau 蛋白病理、突触损失和神经退行性变。该假设将在人类 AD 死后大脑（目标 1）和 3x-Tg-AD 小鼠模型（目标 2）中进行测试其特征是进行性 Aβ 和 tau 病理学。神经元细胞凋亡是 AD 病理学的一个特征，被认为会导致不可逆转的认知能力下降。我们发现酗酒会增加 AD 中已知有神经元损失的大脑区域的神经退行性变，例如我们的研究表明前额叶皮层 (PFC) 和海马体存在促炎 Toll 样受体 (TLR)。我们发现慢性神经元细胞凋亡。暴食乙醇会增加 HMGB1-TLR4 信号传导，激活小胶质细胞分泌促炎性小胶质细胞。我们发现 miRNA let-7b 激活神经元中的 TLR7，Let-7b-TLR7 信号传导诱导神经元细胞凋亡。通过 TNF 受体超家族凋亡诱导配体 (TRAIL) 导致神经元细胞死亡。和 TRAIL 均与 AD 病理学有关，但尚未发现与 AD 神经变性之间的联系。我们发现，长期酗酒会通过增强 TRAIL- 来促进 AD 神经变性。该假设将在人类 AD 死后大脑中进行测试（Aim）。 1) 和 5xFAD AD 小鼠模型（目标 3），其特征是 Aβ 诱导的神经元凋亡。