Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's disease

项目总结/摘要 任何年龄的认知问题的发展都是毁灭性的，但在 有受抚养人的工作年龄人口是一个主要的公共卫生问题。年轻型阿尔茨海默病 疾病（YOAD）定义为在65岁之前出现并且缺乏已知引起的突变的个体。 阿尔茨海默病（AD）病理学。神经病理学和神经影像学研究表明， 在YOAD患者中积累，通常表现为非典型的非遗忘综合征。我们的初步数据 表明tau积累通过缠结承载神经元中的渐进成熟水平发生， 这在YOAD中对皮质的影响不成比例地超过边缘结构。此外，我们显示年轻的年龄 发作与Meynert基底核中更大的缠结积聚和神经元丢失相关 （胆碱能中枢）和蓝斑（去甲肾上腺素能中枢）-两个神经调节中枢涉及早期 疾病的阶段。由于无论年龄大小，均可观察到定型淀粉样β斑块模式， 共病神经病理在YOAD中不太常见，该队列非常适合进行有针对性的研究 选择性的弱点来纠缠AD的病理学。区域对高级缠结成熟度水平的脆弱性 皮质边缘结构和神经调节中枢的改变被假设为综合征异质性的基础 在YOAD中观察。这项赠款的总体目标是揭示区域和细胞脆弱性的特征 通过调查是什么改变了缠结积累的模式， 和小胶质细胞激活。我们的单细胞RNA测序的初步数据强调了以下方面的重要性： 考虑到疾病的异质性和定量神经病理学用于验证基因表达的效用， 变化这项提案旨在通过关注老年人来改变目前的AD研究， 展示了即使在终末期疾病的背景下，区域变异性如何为细胞生物学提供信息。到 完成我们的目标，并促进分层的非典型和典型（遗忘）的临床综合征，MPI 该团队结合了专业知识和资源，积累了最大的记录YOAD队列之一， 有558个大脑组织可供研究。该研究的目的是验证以下假设：1） YOAD脑中tau病理学的神经病理学模式的修饰因子在分层的病例之间存在差异 通过非典型与典型（遗忘）临床综合征，2）最易受AD-tau影响的神经元群体 在皮质边缘区有相似的分子特征，反映了 YOAD，和3）皮质边缘小胶质细胞激活模式在按以下因素分层的YOAD病例的大脑中不同： 非典型与典型（遗忘）临床综合征。该项目的完成将确定特定的细胞群 易受区域性AD-tau病理学的影响，并识别对应于以下的小胶质细胞激活模式的修饰剂： 在YOAD中的积极tau积累。

PROJECT SUMMARY/ABSTRACT Development of cognitive problems at any age is devastating, but development of cognitive problems in working-age people with dependents represents a major public health concern. Young-onset Alzheimer's disease (YOAD) is defined as individuals who present before age 65 and lack mutations known to cause Alzheimer's disease (AD) pathology. Neuropathology and neuroimaging studies demonstrate greater tau accumulation in YOAD who often present with atypical, non-amnestic syndromes. Our preliminary data demonstrates that tau accumulation occurs through progressive maturity levels in tangle-bearing neurons, which disproportionately affects cortical more than limbic structures in YOAD. Moreover, we show younger age onset is associated with greater tangle accumulation and neuronal loss in nucleus basalis of Meynert (cholinergic hub) and locus coeruleus (noradrenergic hub) – two neuromodulatory hubs implicated in early stage of disease. As stereotypic amyloid-β plaque patterns are robustly observed regardless of age, and comorbid neuropathologies are less frequent in YOAD, this cohort is ideally suited for a targeted investigation of selective vulnerabilities to tangle pathology in AD. Regional vulnerabilities to advanced tangle maturity levels in corticolimbic structures and neuromodulatory hubs are hypothesized to underlie the syndromic heterogeneity observed in YOAD. The overall goal of this grant is to uncover signatures of regional and cellular vulnerabilities underlying syndromic heterogeneity in YOAD by investigating what modifies patterns of tangle accumulation and microglial activation. Our preliminary data from single-cell RNA sequencing underscores the importance of considering disease heterogeneity and the utility of quantitative neuropathology for validating gene expression changes. This proposal seeks to shift current research in AD by focusing on younger-aged individuals and demonstrating how regional variability can inform cellular biology even in the context of end-stage disease. To accomplish our goals and facilitate stratification by atypical and typical (amnestic) clinical syndromes, the MPI team has combined expertise and resources to amass one of the largest documented YOAD cohorts totaling 558 brains with available tissue for study. The goal of the grant is to test the following hypotheses: 1) Modifiers of the neuropathologic patterns of tau pathology in YOAD brains differ between cases stratified by atypical vs. typical (amnestic) clinical syndromes, 2) The most vulnerable neuronal populations to AD-tau share a similar molecular signature across corticolimbic regions reflective of syndromic heterogeneity in YOAD, and 3) Corticolimbic microglial activation patterns differ in the brains of YOAD cases stratified by atypical vs. typical (amnestic) clinical syndrome. Completion of this project will identify specific cell populations vulnerable to regional AD-tau pathology and identify modifiers of microglial activation patterns corresponding to aggressive tau accumulation in YOAD.