Atlas for neuronal and glial cell types selectively vulnerable to proteinopathies during progression of Alzheimer's Disease

在阿尔茨海默病进展过程中选择性易受蛋白质病影响的神经元和神经胶质细胞类型图谱

• 批准号: 10667245
• 负责人: KUO-FEN LEE
• 金额: $ 279.07万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667245
• 关键词: ATAC-seq; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Astrocytes; Atlases; BRAIN initiative; Bar Codes; Biological Markers; Brain; Brain region; Cell Nucleus; Cells; Censuses; Cerebellum; Clinical; Complement; Complex; Data; Data Set; Detection; Disease Progression; Electrophysiology (science); Event; Female; Fluorescent in Situ Hybridization; Genes; Goals; Hippocampus; Human; Impaired cognition; Impairment; Knock-in; Knock-in Mouse; Maps; Memory impairment; Microglia; Molecular; Molecular Profiling; Mus; Mutate; Neocortex; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Norepinephrine; Oligodendroglia; Pathogenesis; Pattern; Phase; Physiological; Play; Population; Predisposition; Prefrontal Cortex; Property; Resolution; Role; Series; Signal Transduction; Slice; Source; Staging; TREM2 gene; Tauopathies; Time; age related; cell type; clinical diagnosis; differential expression; entorhinal cortex; epigenomics; excitatory neuron; gene network; genetic variant; inhibitory neuron; insight; locus ceruleus structure; male; multi-scale modeling; multimodality; multiple omics; neocortical; nerve supply; neuron loss; neuropathology; novel; pre-clinical; prepulse inhibition; prodromal Alzheimer' s disease; promoter; response; risk variant; sex; spatiotemporal; tau Proteins; tau-1; transcriptome sequencing; transcriptomics

Abstract The long-term goal of this project is to elucidate multimodal mechanisms underlying selective vulnerability of neuronal and non-neuronal cells to proteinopathies during the progression of Alzheimer's Disease (AD). The most notable feature of AD is its strikingly age- and sex-dependent regional onset and progression–selective vulnerability–which is manifest in distinct clinical presentations, e.g., memory impairment in AD and patterns of brain degeneration. Recent studies on the staging of AD neuropathology showed AD-related tauopathy begins in the locus coeruleus (LC), followed by neurofibrillary tangles in the entorhinal cortex (EC), followed by hippocampal (HC), and then neocortex, e.g., prefrontal cortex (PFC). One hypothesis for selective vulnerability is that major AD risk genes are regionally restricted, but the results show they are rather broadly expressed. A body of evidence support that glia play multiple essential roles at different brain region in AD pathogenesis. These data suggest that selective vulnerability is likely a result of interplay of intrinsic properties of neurons and glial cells in their response to proteinopathies in a dynamic and spatiotemporal manner at vulnerable brain regions. For example, EC neurons project multiple brain regions including the EC, PFC and cerebellum. Yet, degeneration of EC and PFC occurs at different stages. In contrast, the cerebellum is largely not affected. There is emerging evidence that subpopulations of microglia treat excitatory and inhibitory neurons differently. Could different glial cell types or differential response to proteinopathies in different projecting sources and/or targets contribute to selective vulnerability? These results underscore the central importance of understanding the diversity of cell types and molecular signature differences in both sexes at spatiotemporal, single-cell resolution and multimodal scales between vulnerable and less vulnerable neuronal and glial populations susceptible to proteinopathies in AD. MAPTS305N;Int10+3 and APPNL-F knock-in (KI) AD mice displaying Tau and Aβ proteinopathies, respectively, will be used to achieve this goal. Preliminary results were obtained to support the project. First, barcoded single-neurons brain-wide projection mapping in controls demonstrates sex- and age- dependent differences in projections of LC neurons to selective targets. The results showed reciprocal innervations among these four brain regions. Second, the analysis of 16-month-old control and APPNL-F mice showed aberrant innervation patterns by norepinephrine (NE) neurons. Third, impaired prepulse inhibition (PPI) has been suggested to be a biomarker for prodromal AD. Importantly, PPI impairment was observed in the 5-month-old APPNL-F mice. Finally, single nuclei (sn)-RNAseq of the EC from 16-month-old control and APPNL-F mice showed selective loss of neuronal and non-neuronal cell types and differential expression of a list of genes, including those associated with neuronal and glial function and impaired PPI. Sn-transcriptomics and-epigenomics will be employed to identify vulnerable cell types followed by spatial transcriptomics to investigate spatiotemporal correlation between proteinopathies and vulnerable cell types and gene networks.

抽象的 该项目的长期目标是阐明选择性脆弱性背后的多模式机制 在阿尔茨海默氏病 (AD) 的进展过程中，神经元和非神经元细胞发生蛋白质病变。这 AD 最显着的特征是其显着的年龄和性别依赖性区域发病和进展选择性 脆弱性——这体现在不同的临床表现中，例如 AD 中的记忆障碍和 大脑退化。最近关于 AD 神经病理学分期的研究表明 AD 相关的 tau 蛋白病开始出现 蓝斑 (LC) 中，然后是内嗅皮层 (EC) 中的神经原纤维缠结，然后是 海马 (HC)，然后是新皮质，例如前额皮质 (PFC)。选择性脆弱性的一种假设 主要的 AD 风险基因受到区域限制，但结果显示它们的表达相当广泛。一个 大量证据表明神经胶质细胞在 AD 发病机制中的不同大脑区域发挥着多种重要作用。 这些数据表明，选择性脆弱性可能是神经元内在特性相互作用的结果 和神经胶质细胞在脆弱大脑中以动态和时空方式对蛋白质病做出反应 地区。例如，EC 神经元投射多个大脑区域，包括 EC、PFC 和小脑。然而， EC和PFC的退化发生在不同的阶段。相比之下，小脑基本上不受影响。 越来越多的证据表明，小胶质细胞亚群以不同的方式处理兴奋性和抑制性神经元。 不同的神经胶质细胞类型或对不同投射来源的蛋白质病的不同反应和/或 目标会导致选择性脆弱性吗？这些结果强调了理解的核心重要性 时空、单细胞中细胞类型的多样性和两性分子特征的差异 脆弱和不易脆弱的神经元和神经胶质群体之间的分辨率和多模式尺度 易患 AD 中的蛋白质病。 MAPTS305N；Int10+3 和 APPNL-F 敲入 (KI) AD 小鼠显示 Tau 和 Aβ 蛋白质病将分别用于实现这一目标。已获得初步结果支持 项目。首先，对照中的条形码单神经元全脑投影映射显示了性别和年龄 LC 神经元对选择性目标的投射存在依赖性差异。结果显示互为 这四个脑区之间的神经支配。二、16月龄对照小鼠和APPNL-F小鼠的分析 显示去甲肾上腺素（NE）神经元的异常神经支配模式。三、前脉冲抑制受损 (PPI) 被认为是 AD 前驱期的生物标志物。重要的是，观察到 PPI 受损 5 个月大的 APPNL-F 小鼠。最后，来自 16 个月大对照的 EC 的单核 (sn)-RNAseq 和 APPNL-F 小鼠表现出神经元和非神经元细胞类型的选择性丢失以及一系列的差异表达 基因，包括与神经元和神经胶质功能以及 PPI 受损相关的基因。 Sn转录组学 和-表观基因组学将用于识别脆弱的细胞类型，然后通过空间转录组学来识别 研究蛋白质病与脆弱细胞类型和基因网络之间的时空相关性。