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

基本信息

批准号：
10431698
负责人：
M MARGARITA BEHRENS
金额：
$ 287.64万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
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/10431698
关键词：
ATAC-seq Address Adrenergic Agents Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos 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 (Brain)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 base cell type connectome entorhinal cortex epigenetic profiling epigenomics genetic variant healthy aging insight locus ceruleus structure male multi-scale modeling multiple omics neuropathology novel promoter relating to nervous system response screening transcriptome transcriptome sequencing transcriptomics

项目摘要

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识别电路特定的细胞类型——细胞规模连接组—— 选择性地容易受到细胞体或轴突连接损失或转录组变化的影响健康衰老和阿尔茨海默病 (AD) 进展过程中单个神经元的特征。有证据表明，关于细胞尺度连接组变化的知识——细胞类型特异性电路将单细胞转录组与大脑连接相结合——是全面理解衰老和 AD 所必需的并为解决这些老化和 AD 变化提供了实验上易于处理的基础。相关的变化可能包括细胞类型、连接性的丧失或转录组特征的改变。这里采用的方法是检验以下假设：存在衰老或 AD 状态特异性的神经和驱动衰老和 AD 进展的分子回路大量证据表明 AD 是一种疾病。一种异质性多因素疾病，选择性影响某些大脑区域，例如内嗅皮层 (EC)，而其他区域，例如小脑，并未受到影响。神经病理学显示 AD 相关的神经病理学始于蓝斑 (LC) 或 EC，随后是海马体 (HC)，然后是前额皮质 (PFC)，LC 包含肾上腺素能 (NA) 和非肾上腺素能。去甲肾上腺素能神经元并提供整个大脑的主要 NA 输入。分期显示，LC 中出现缠结，NA 激活已显示可改善 AD EC 为 HC 提供关键的皮质输入，这对于学习记忆至关重要。提供对各种高阶函数的自上而下的调节，但基于细胞类型的输入和/或输出。由于衰老是一个主要因素，因此在单个神经元水平上选择性脆弱的网络尚不清楚。 AD 的危险因素，有选择地了解是否存在不同、相似或重叠非常重要该项目将逆行标记与衰老和 AD 之间的脆弱电路特异性细胞类型结合起来。多组学 sn-RNAseq 和 sn-ATACseq 将细胞类型的转录组和表观基因组特性与神经投射并研究与衰老和 AD 进展相关的电路特异性变化雄性和雌性对照小鼠以及 AD 小鼠的四个大脑区域，即 LC、EC、HC 和 PFC。小鼠，APPNLF 小鼠品系——携带淀粉样前体蛋白基因的敲入人类突变，并且，重要的是，表达 Aβ 的生理水平，模仿晚发性 AD——将使用来自此的数据。该项目将为易受退化和/或改变的神经元类型提供新的见解空间和时间方式的分子/信号特征网络及其相关性这种方法是建立多尺度模型的重要一步。这将有助于填补遗传变异（例如 APP、AOPE 或 TREM2）对大脑影响之间的空白衰老和 AD 中的分子网络拓扑。