Cell-type specific risk and resilience in Alzheimer’s disease and aging

阿尔茨海默病和衰老中的细胞类型特定风险和恢复能力

基本信息

批准号：
10213995
负责人：
ANIRBAN PAUL
金额：
$ 219.46万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213995
关键词：
3xTg-AD mouse Adopted Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Anatomy Animal Diseases Architecture Area Autopsy Behavior Control Behavioral Bioinformatics Biological Blood Vessels Brain Brain Mapping Brain Stem Brain imaging Categories Cell Survival Cells Code Communication Crows Custom Cytology Data Dementia Disease Disease Progression Enzymes Fluorescence Microscopy Functional disorder Gene Expression Gene Family Genes Gliosis Heparin Heparitin Sulfate Hippocampus (Brain)Histologic Human Impaired cognition In Situ Interneurons Knowledge Label Late Onset Alzheimer Disease Light Longevity Measures Microscopy Molecular Morphology Mus Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Pathologic Pathology Pathway interactions Physiological Predisposition Property RNA Regimen Resolution Risk Risk Factors Sampling Senile Plaques Specific qualifier value Sulfate Synapses Systems Biology Taxonomy Testing Time Transcript Ursidae Family Vulnerable Populations age related bioinformatics tool brain cell cell type density differential expression disease phenotype entorhinal cortex excitatory neuron frontal lobe genetic makeup glycosylation healthy aging hippocampal pyramidal neuron imaging study inhibitory neuron innovation morphometry neural circuit novel resilience response sex single-cell RNA sequencing sulfurtransferase survivorship transcriptome transcriptomics

项目摘要

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with distinct histological and behavioral hallmarks but its cell-type basis is not clear. Recent discoveries now provide compelling rationale that constituent cell types bear a non-uniform risk profile as a function of disease and age. Human post- mortem study showed inhibitory interneurons (IN) and excitatory pyramidal neurons (IN) undergo differential alterations in gene expression in AD and mouse brain imaging study observed progressive cytological dedifferentiation of synapse architecture due to aging. These results dovetail with our discovery that the differential expression of six gene categories, synergistically involved in synaptic communication specifies neuron-type identity and their diverse morpho-physiological properties. Our central hypothesis is that the distinct transcriptomic identity that bestows unique cell-type properties also confers an inherent risk and resilience to AD risk factors, such as age, sex and genetic makeup. We posit that an altered cell-type specific transcriptome underlies the disparate response of inhibitory and excitatory neuron subtypes in AD and the dedifferentiation of synapses in aging. Through cross-disciplinary systems biology approaches we will identify the vulnerable cell-types in AD, establish cell-type specific AD signatures and further investigate biological relationship between healthy aging and AD pathology. Aim-1 will test the hypothesis that diverse brain cell subclasses confers differential risk through distinct transcriptomic response to progressive stages of AD and aging. A subclass specific longitudinal approach will allow us to prioritize for cells that are fundamental to the genesis of AD. We will determine age-dependent vulnerability in 3xTg-AD mouse by single- cell RNA-Seq (scRNA-Seq) of eight genetically labeled subclass in three major AD associated brain areas, brain-stem, entorhinal cortex, hippocampus and frontal cortex at 3, 6 and 15 months. Aim-2 will test the hypothesis that excitatory PNs and inhibitory INs have differential anatomical, morphological and cell survival trajectories in AD and aging. Synapses in neural circuits control behavior and their progressive dedifferentiation have been implicated in aging and dementia. As the molecular composition of synapses are distinct for each neuron-type they will be differentially impacted by AD and age. We will perform whole brain light-sheet microscopy on PN and IN in 3xTg-AD mouse across three time points 3, 6 and 15 months to capture the subclass specific dynamics of progressive pathological changes in AD. Aim-3 will test the hypothesis that cell specific glycosylation codes confers vulnerability to proteinopathy in AD and aging. Plaques and neurofibrillary tangles are AD hallmarks, however cell specific vulnerability is unknown. Differential expression of heparin sulfate (HS) enzymes create HS diversity akin to a “glycosylation code” that predisposes some cells to form aggregates while protecting others. In 3xTg-AD multiplexed RNA in-situ will measure HS biosynthetic enzyme transcripts, as a function of healthy aging and in pathology.

【摘要】：阿尔茨海默病(AD)是一种进行性神经退行性疾病,具有独特的组织学和病理学特征。行为特征，但其细胞类型基础尚不清楚。最近的发现提供了令人信服的理由。组成细胞类型随着人类疾病和年龄的变化而具有不均匀的风险特征。尸检研究显示抑制性中间神经元 (IN) 和兴奋性锥体神经元 (IN) 存在差异 AD 基因表达的改变和小鼠脑成像研究观察到的渐进细胞学由于衰老导致的突触结构去分化。这些结果与我们的发现相吻合。六个基因类别的差异表达，协同参与突触通讯指定我们的中心假设是神经元类型的同一性及其不同的形态生理特性。独特的转录组特性赋予了独特的细胞类型特性，同时也带来了固有的风险和我们认为，细胞类型特异性的改变会增强对 AD 风险因素（例如年龄、性别和基因组成）的抵抗力。转录组是 AD 中抑制性和兴奋性神经元亚型不同反应的基础通过跨学科的系统生物学方法，我们将确定衰老过程中突触的去分化。 AD 中的脆弱细胞类型，建立细胞类型特异性 AD 特征并进一步研究生物学 Aim-1 将检验脑细胞多样化的假设。亚类通过对进展阶段的不同转录组反应赋予不同的风险 AD 和衰老。子类特定的纵向方法将使我们能够优先考虑哪些细胞。我们将通过单-确定 3xTg-AD 小鼠的年龄依赖性脆弱性。 AD 相关大脑区域的 8 个基因标记亚类的细胞 RNA 测序 (scRNA-Seq)， Aim-2 将在 3、6 和 15 个月时对脑干、内嗅皮层、海马体和额叶皮层进行测试。假设兴奋性 PN 和抑制性 IN 具有解剖学、形态学和细胞差异 AD 和衰老中的生存轨迹神经回路中的突触控制行为及其进展。由于突触的分子组成不同，去分化与衰老和痴呆有关。每种神经元类型都不同，它们会受到 AD 和年龄的不同影响。我们将进行整个大脑的研究。在 3xTg-AD 小鼠的 3、6 和 15 个月三个时间点上对 PN 和 IN 进行光片显微镜观察 Aim-3 将捕获 AD 进展性病理变化的亚类特定动态。假设细胞特异性糖基化代码导致 AD 和蛋白质病的易感性斑块和神经原纤维缠结是 AD 的标志，但细胞特定的脆弱性尚不清楚。硫酸肝素 (HS) 酶的差异表达会产生类似于“糖基化代码”的 HS 多样性，在 3xTg-AD 中，原位多重 RNA 会促使某些细胞形成聚集体。测量 HS 生物合成酶转录本，作为健康衰老和病理学的函数。