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

项目摘要/摘要 任何年龄的认知问题的发展都是毁灭性的，但认知问题的发展在 有家属的适龄劳动人口是一个主要的公共卫生问题。青年起病阿尔茨海默氏症 疾病(Yoad)被定义为在65岁之前出现并且缺乏已知引起的突变的个人 阿尔茨海默病(AD)病理学。神经病理学和神经成像研究显示更大的tau 在约阿德积聚，通常表现为非典型的非遗忘症候群。我们的初步数据 证明tau的积累是通过缠结神经元中逐渐成熟的水平发生的， 在约阿德，这对皮质结构的影响比对边缘结构的影响更大。此外，我们表现出更年轻的年龄 发病与Meynert基底核较大的缠结堆积和神经元丢失有关 (胆碱能中枢)和蓝斑(去甲肾上腺素能中枢)--两个神经调节中枢与早期 疾病的阶段。由于刻板的淀粉样蛋白-β斑块模式无论年龄长短都能被强有力地观察到，并且 合并神经病变在约阿德较少发生，这一队列非常适合进行有针对性的研究 有选择性的弱点，使AD的病理发生纠结。地区对高级成熟度级别的脆弱性 在皮质边缘结构和神经调节中枢被认为是综合症异质性的基础。 在约阿德观察到的。这项拨款的总体目标是发现区域性和蜂窝漏洞的特征。 Yoad中潜在的综合征异质性--通过研究是什么改变了缠绕堆积的模式 和小胶质细胞的激活。我们来自单细胞RNA测序的初步数据强调了 考虑疾病异质性和定量神经病理学验证基因表达的有效性 改变。这项建议寻求通过将重点放在更年轻的个体和 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。至 通过非典型和典型(遗忘症)临床症状实现我们的目标并促进分层，MPI 团队结合了专业知识和资源，积累了最大的有记录的Yoad队列之一 558个大脑中有可供研究的组织。这笔赠款的目的是检验以下假设：1) Yoad脑中tau病理的神经病理模式的修饰物在不同的分层病例中不同 根据非典型与典型(遗忘症)临床症状，2)AD-tau最脆弱的神经元群体 在皮质边缘区域共享相似的分子特征，反映了综合征的异质性 Yoad，以及3)Yoad患者大脑中皮质边缘小胶质细胞的激活模式不同，按 不典型与典型(健忘症)临床综合征。该项目的完成将确定特定的细胞群体 易受局部AD-tau病理的影响，并确定与以下相关的小胶质细胞激活模式的修饰物 在约阿德积聚了大量的tau。

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.