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

研究年轻发病阿尔茨海默病中 tau 病理学的区域和细胞脆弱性

• 批准号: 10369782
• 负责人: BERNARDINO Francesco GHETTI
• 金额: $ 306.77万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369782
• 关键词: Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Area; Astrocytes; Basal Nucleus of Meynert; Biological; Brain; Brain region; Cells; Cellular biology; Cessation of life; Clinical; Data; Disease; Environment; Evaluation; Gene Expression; Gene Expression Profile; Goals; Grant; Heterogeneity; Hippocampus (Brain); Human; Individual; Inflammation; Investigation; Late Onset Alzheimer Disease; Lesion; Lewy Body Disease; Maps; Measures; Methods; Microglia; Modeling; Molecular; Molecular Profiling; Morphology; Mutation; Nature; Nerve Degeneration; Neurobiology; Neurofibrillary Tangles; Neurons; Onset of illness; Pathology; Pathway interactions; Pattern; Persons; Population; Primary Progressive Aphasia; Public Health; Reporting; Research; Resources; Senile Plaques; Series; Severities; Stratification; Structure; Symptoms; Syndrome; Technology; Testing; Tissues; Traumatic Brain Injury; Vulnerable Populations; aged; association cortex; cell type; cholinergic; cognitive development; cohort; comorbidity; corticobasal syndrome; demographics; digital; digital pathology; disease heterogeneity; end stage disease; entorhinal cortex; experience; innovation; locus ceruleus structure; neuroimaging; neuron loss; neuronal patterning; neuropathology; neuroregulation; neurotoxicity; noradrenergic; protein TDP-43; protein expression; sex; single-cell RNA sequencing; tau Proteins; tau aggregation; transcriptomics

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.

项目概要/摘要 在任何年龄出现认知问题都是毁灭性的，但在不同年龄阶段出现认知问题 有家属的工作年龄人口是一个主要的公共卫生问题。年轻发病的阿尔茨海默病 疾病 (YOAD) 被定义为 65 岁之前出现且缺乏已知可导致疾病的突变的个体 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 tau 蛋白更大 YOAD 中的积累通常表现为非典型、非遗忘综合征。我们的初步数据 表明 tau 蛋白的积累是通过具有缠结的神经元的逐渐成熟水平而发生的， 在 YOAD 中，它对皮质的影响比对边缘结构的影响更大。而且还显年轻 发病与 Meynert 基底核中更大的缠结积累和神经元损失有关 （胆碱能中枢）和蓝斑（去甲肾上腺素能中枢）——与早期有关的两个神经调节中枢 疾病阶段。由于无论年龄如何，都会强烈观察到刻板的淀粉样蛋白-β斑块模式，并且 YOAD 中共病神经病理学较少发生，该队列非常适合有针对性的研究 AD 中缠结病理学的选择性脆弱性。高级缠结成熟度级别的区域漏洞 假设皮质边缘结构和神经调节中枢是综合征异质性的基础 在 YOAD 中观察到。这笔赠款的总体目标是发现区域和细胞漏洞的特征 通过研究什么改变了缠结积累的模式，揭示了 YOAD 中潜在的综合征异质性 和小胶质细胞激活。我们从单细胞 RNA 测序中得到的初步数据强调了 考虑疾病异质性和定量神经病理学在验证基因表达方面的效用 变化。该提案旨在通过关注年轻个体和 展示即使在终末期疾病的情况下，区域变异如何为细胞生物学提供信息。到 实现我们的目标并促进按非典型和典型（遗忘）临床综合征进行分层，MPI 团队结合了专业知识和资源，聚集了最大的记录在案的 YOAD 队列之一，总计 558 个大脑以及可供研究的组织。拨款的目的是检验以下假设：1) YOAD 大脑中 tau 病理学神经病理学模式的修饰因素在分层病例之间有所不同 根据非典型与典型（遗忘）临床综合征，2) 最容易受到 AD-tau 影响的神经元群体 皮质边缘区域具有相似的分子特征，反映了综合征的异质性 YOAD，以及 3) YOAD 病例大脑中皮质边缘小胶质细胞的激活模式不同，按 非典型与典型（遗忘）临床综合征。该项目的完成将鉴定特定的细胞群 容易受到区域 AD-tau 病理学的影响，并确定对应于小胶质细胞激活模式的修饰因子 YOAD 中积极的 tau 蛋白积累。