Circuit-specific cell types in aging and Alzheimer's disease

衰老和阿尔茨海默病中的电路特异性细胞类型

• 批准号: 10625916
• 负责人: M MARGARITA BEHRENS
• 金额: $ 284.45万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625916
• 关键词: ATAC-seq; Address; Adrenergic Agents; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anatomy; Animals; Area; Atlases; Axon; BRAIN initiative; Behavioral; Biochemical; Brain; Brain region; Cell Count; Cell Nucleus; Cell Separation; Cells; Censuses; Cerebellum; Cognition; Coupling; Data; Data Set; Deterioration; Disease; Disease Progression; Down-Regulation; Electrophysiology (science); Female; Gene Proteins; Genetic Diseases; Goals; Hippocampus; Human; Impaired cognition; Individual; Joints; Knock-in; Knowledge; Label; Late Onset Alzheimer Disease; Learning; Link; Location; Maps; Memory; Molecular; Morphology; Mus; Mutation; Neurofibrillary Tangles; Neurons; Nuclear Envelope; Output; Physiological; Prefrontal Cortex; Property; Recombinant adeno-associated virus (rAAV); Resolution; Senile Plaques; Signal Transduction; Source; Staging; System; TREM2 gene; Testing; age effect; cell type; connectome; entorhinal cortex; epigenetic profiling; epigenomics; genetic variant; healthy aging; insight; locus ceruleus structure; male; multi-scale modeling; multiple omics; neural; neuropathology; novel; promoter; response; screening; transcriptome; transcriptome sequencing; transcriptomics

Abstract The long-term goal of this project is to define and identify circuit-specific cell types–cellular scale connectome– that are selectively vulnerable to loss of cell bodies or axonal connections or change of transcriptomic signatures of individual neurons during the progression of healthy aging and Alzheimer's disease (AD). Evidence suggests that knowledge on the change of cellular scale connectomes–cell type-specific circuits by coupling single cell transcriptome with brain connectivity– is needed for holistic understanding of aging and AD and provides an experimentally tractable basis to address longitudinal changes. These aging- and AD- associated changes may include loss of cell types, connectivity or alterations in transcriptomic signatures. This approach employed here is to test the hypothesis that there are aging- or AD state-specific neural and molecular circuits that drive the progression of aging and AD. A large body of evidence demonstrates that AD is a heterogeneous, multifactorial disease that selectively affects certain brain regions, e.g. the entorhinal cortex (EC), while other areas, such as the cerebellum, remain unaffected. Recent studies on the staging of AD neuropathology showed AD-related neuropathology begins in the locus coeruleus (LC) or the EC, followed by the hippocampus (HC) and then the prefrontal cortex (PFC). The LC contains both adrenergic (NA) and non- noradrenergic neurons and provides the major NA inputs throughout the entire brain. Neuropathological staging has shown that tangles fist appear in the LC and NA activation has been shown to ameliorate AD deficits. The EC provides key cortical inputs to the HC, which is essential in learning memory. The PFC provides the top-down regulation on various higher order functions. But cell types-based input and/or output networks that are selectively vulnerable at the single neurons level are not well understood. As aging is a major risk factor for AD, it is important to understand whether there are distinct, similar or overlapping selectively vulnerable circuit-specific cell types between aging and AD. This project is to combine retrograde labeling with multiomic sn-RNAseq and sn-ATACseq to link transcriptomic and epigenomic properties of cell types to neuronal projections and investigate circuit-specific changes associated with progression of aging and AD in four brain regions, namely the LC, EC, HC and PFC, in both male and female control and AD mice. For AD mice, the APPNLF mouse line–that carries knockin human mutations in the amyloid precursor protein gene and, importantly, expresses physiological levels of Aβ, mimicking late onset AD–will be used. The data from this project will provide novel insights on the types of neurons vulnerable to degeneration and/or alterations of molecular/signaling signature networks in a spatial and temporal fashion and the correlation with neuropathology and cognitive impairment. This approach is a major step toward establishing multiscale models that will help to fill the gap between the effects of genetic variants (e.g., APP, AOPE or TREM2) on brain topology with molecular networks in aging and AD.

抽象的 该项目的长期目标是定义和确定电路特异性细胞类型 - 细胞尺度连接组 - 有选择地易受细胞体或轴突连接或转录组的变化的影响 在健康衰老和阿尔茨海默氏病（AD）进展过程中，个别神经元的签名。 有证据表明，通过细胞尺度连接组的变化 - 细胞类型特异性电路的知识 将单细胞转录组与大脑连接性耦合 - 对衰老和AD的整体了解是必需的 并提供了一个可以解决纵向变化的实验典型基础。这些老化和广告 相关的更改可能包括损失细胞类型，连通性或转录组特征的改变。这 这里采用的方法是检验以下假设： 驱动衰老和AD进展的分子电路。大量证据表明AD是 一种异质的多因素疾病，有选择地影响某些大脑区域，例如内河皮质 （EC），而其他区域（例如小脑）仍然不受影响。关于AD分期的最新研究 与广告相关的神经病理学的神经病理学始于核座（LC）或EC，其次是 海马（HC），然后是前额叶皮层（PFC）。 LC同时包含肾上腺素（NA）和非 - 去肾上腺素能神经元，并在整个大脑中提供主要的NA输入。神经病理学 分期表明，缠结拳头出现在LC中，NA激活已显示为改善AD 缺陷。 EC为HC提供了关键的皮质输入，这对于学习记忆至关重要。 PFC 提供有关各种高阶功能的自上而下的调节。但是基于单元类型的输入和/或输出 在单个神经元级别有选择性易受伤害的网络尚不清楚。因为衰老是主要的 AD的危险因素，重要的是要理解有选择性，相似还是重叠 老化和AD之间的脆弱电路特异性电池类型。这个项目是将逆行标签与 多素SN-RNASEQ和SN-ATACSEQ将细胞类型的转录组和表观基因组特性链接到 神经元项目并研究与衰老和AD进展相关的电路特异性变化 男性和女性对照和AD小鼠的四个大脑区域，即LC，EC，HC和PFC。对于广告 小鼠，AppNLF小鼠系 - 该系列携带淀粉样前体蛋白基因中的敲击人类突变，并且 重要的是，将使用表达Aβ的物理水平，模仿晚期发作 - 将使用。来自此的数据 项目将提供有关易受变性和/或改变的神经元类型的新见解。 分子/信号传导签名网络以空间和临时的方式以及与 神经病理学和认知障碍。这种方法是建立多尺度模型的主要一步 这将有助于填补遗传变异的影响（例如App，AOPE或TREM2）之间的空白 拓扑具有分子网络在衰老和AD中。