Novel mechanism of alcohol self-administration and relapse

项目摘要/摘要 阿尔茨海默病(AD)及其相关痴呆(AD/ADRD)是一组不可逆转的进行性痴呆 神经退行性疾病是美国痴呆症最常见的原因。Tau- 相关的AD/ADRD神经病理起源于内嗅皮层(EC)，并扩散到海马区 (HPC)和其他相连的大脑区域，随着疾病严重程度的进展。尽管饮酒和饮酒之间的联系 和Tau相关的病理学已经建立，这种独特相互作用的基础机制是 没有完全理解。在这份行政副刊中，我们建议通过以下方式解决这一知识差距 扩展亲本R01以评估长期饮酒(12周)与基因组的相互作用 应用创新的人类AAV策略研究AD/ADRD神经病理学的发展和进展 Tau-P301L(huTau-P301L)在C57BL/6J小鼠EC内“种植”。我们建议利用GeoMx数字空间 通过下一代测序(NGS)进行量化的分析(DSP)，以评估 饮酒和huTau-P301L在神经元和神经细胞转录组(&gt；18000个基因)上的表达 EC、海马体和其他相互连接的脑区的神经胶质细胞。我们还将评估病理性huTau-P301 在EC中的表达，传播(扩散)到HPC和其他核，Tau错误折叠和Tau(AT8) 一项平行的免疫组织化学研究中的过度磷酸化。这些独立但综合的研究可以是 在母公司R01的1年期间进行。这项工作建立在强大的初步数据基础上 根据先前的一项研究表明，饮酒会导致早期发病和病理性疾病的显著增加 人Tau-AT8在海马区的磷酸化被时间锁定，起病早且增加 3xTg-AD小鼠海马区依赖认知缺陷的程度。鉴于这一突出的参与 在我们之前的酒精研究中，tau被广泛认为是AD/ADRD的关键机制，我们 预测拟议的研究很有可能识别出酒精的独特转录足迹 这导致了AD/ADRD的病理改变。识别AD/ADRD背后的酒精的新神经靶点 病理学有可能导致特定的诊断和治疗策略。

Project Summary/Abstract Alzheimer's disease (AD) and its related dementias (AD/ADRD) are a set of irreversible and progressive neurodegenerative disorders that represent the most common cause of dementia in the United States. Tau- associated AD/ADRD neural pathology originates in the entorhinal cortex (EC) and spreads to the hippocampus (HPC) and other connected brain regions as disease severity progresses. Although links between alcohol use and Tau-associated pathology have been established, the mechanisms that underlie this unique interaction are not fully understood. In this Administrative Supplement, we propose to address this gap in knowledge by expanding the parent R01 to evaluate the genomic interaction between chronic alcohol drinking (12-weeks) and the development and progression of AD/ADRD neural pathology using an innovative AAV strategy for human Tau-P301L (huTau-P301L) “seeding” in the EC of C57BL/6J mice. We propose to utilize GeoMx Digital Spatial Profiling (DSP) with quantification by next-generation sequencing (NGS) to evaluate the interaction between alcohol drinking and huTau-P301L expression on the whole transcriptome (>18,000 genes) from neurons and glia in the EC, hippocampus, and other connected brain regions. We will also evaluate pathological huTau-P301 expression in the EC, propagation (spread) to the HPC and other nuclei, Tau misfolding, and Tau (AT8) hyperphosphorylation in a parallel immunohistochemistry study. These separate but integrated studies can be conducted during a 1-year period of the parent R01. This work is based on strong preliminary data generated under a prior project showing that alcohol drinking produced an early onset and profound increase in pathological human Tau-AT8 phosphorylation in the hippocampus that were time-locked with early onset and increased magnitude of hippocampal-dependent cognitive deficits in 3xTg-AD mice. Given this prominent involvement of Tau in our prior alcohol studies and its widely acknowledged function as a key mechanism of AD/ADRD, we predict that the proposed studies have a high probability of identifying a unique transcriptomic footprint of alcohol that contributes to AD/ADRD pathology. Identifying novel neural targets of alcohol that underlie AD/ADRD pathology has potential to lead to specific diagnostic and therapeutic strategies.