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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，具有不同的组织学和 行为标志，但其细胞类型的基础尚不清楚。最近的发现提供了令人信服的理由 构成细胞类型的风险特征是疾病和年龄的函数。人类邮政 - Mortem研究表明抑制性中间神经元（IN）和兴奋性锥体神经元（IN）经历差异 AD和小鼠脑成像研究中基因表达的改变观察到进行性细胞学 由于衰老而导致的突触结构的去分化。这些结果与我们发现 六个基因类别的差异表达，协同参与突触通信规范 神经型身份及其潜水形态生理特性。我们的核心假设是 赋予独特的细胞类型属性的独特转录组身份也承认继承风险和 对AD风险因素（例如年龄，性别和遗传构成）的韧性。我们肯定的是细胞类型特异性改变 转录组是AD和抑制性神经元亚型的不同反应和 衰老中突触的去分化。通过跨学科系统生物学方法，我们将确定 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 健康衰老与AD病理学之间的关系。 AIM-1将测试潜水脑细胞的假设 子类通过对渐进阶段的不同转录组的反应来承认差异风险 广告和老化。亚类特定的纵向方法将使我们能够优先考虑 AD起源的基础。我们将通过单个 - 在三个主要AD相关的大脑区域中的八个普通标记子类的细胞RNA-SEQ（SCRNA-SEQ）， 在3、6和15个月时，脑干，内嗅皮层，海马和额叶皮层。 AIM-2将测试 兴奋性PN和抑制性INS具有差异解剖学，形态和细胞的假设 广告和衰老中的生存轨迹。神经元电路中的突触控制行为及其渐进性 在衰老和痴呆症中已暗示了去分化。由于突触的分子组成是 对于每种神经类型，它们都会受到AD和年龄的不同影响。我们将执行整个大脑 在三个时间点3、6和15个月内，PN和3XTG-AD小鼠的光显微镜 捕获AD进行性病理变化的子类特定动力学。 AIM-3将测试 假设细胞特异性糖基化代码承认AD中对蛋白质病的脆弱性 老化。斑块和神经原纤维缠结是AD标志，但是细胞特异性脆弱性尚不清楚。 硫酸肝素（HS）酶的差异表达产生类似于“糖基化代码”的HS多样性 容易使某些细胞形成聚集体，同时保护其他细胞。在3XTG-AD多路复用的RNA中，原位将 测量HS生物合成酶转录本作为健康衰老和病理学的函数。