Sex-Specific Single Cell Expression Profiles, Genetic Risk and Drug Responsiveness in Alzheimer's Disease

阿尔茨海默病的性别特异性单细胞表达谱、遗传风险和药物反应

• 批准号: 10467589
• 负责人: Sourav Ghosh
• 金额: $ 125.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467589
• 关键词: Affect; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Architecture; Autopsy; Biological; Brain; Brain region; Cell Nucleus; Cells; Clinical Trials; Coupled; Data; Data Collection; Dependence; Development; Disease; Disease susceptibility; Enrollment; Female; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Transcription; Goals; Heterogeneity; Histologic; Human; Human Genetics; Immune; Impaired cognition; Inflammatory; Knock-in; Knock-in Mouse; Knowledge; Late Onset Alzheimer Disease; Learning; MERTK gene; Memory; Microglia; Molecular; Morphology; Mus; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Prevention therapy; Receptor Protein-Tyrosine Kinases; Recovery; Reporting; Resolution; Risk; Role; Severities; Sex Differences; Small Nuclear RNA; Structure of middle temporal gyrus; Synapses; Testing; Therapeutic; Therapeutic Intervention; Treatment Effectiveness; Variant; Woman; aged; brain cell; brain tissue; cell type; cohort; disease phenotype; drug development; effective intervention; effective therapy; experimental study; gain of function; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; human data; insight; male; men; mouse model; neuroinflammation; novel; preservation; response; risk variant; sex; tau aggregation; tool; transcriptome sequencing; transcriptomics; treatment response

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by progressive cognitive decline coupled with accumulation of brain amyloid-ß and tau aggregates. Despite being the most common neurodegenerative disease, there is no effective treatment available to slow or halt the fatal progression of AD. Two thirds of AD patients are females, and women have a higher risk of developing AD. Women with AD have more extensive brain histological changes than men with AD, more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects female and male brains differentially. Despite evident AD sex variance, the mechanisms and pathways are still poorly understood. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions and to develop sex-specific therapies. We hypothesize that female and male brains present critically distinct disease susceptibilities and responses to AD pathology, specifically with regard to immune architecture and CNS synapse plasticity. Our Preliminary single nucleus RNA sequencing (snRNA-seq) profiles of post-mortem human AD brains revealed sex-specific differences in cellular composition and neuroinflammatory features. We identified marker gene sets for AD- associated female-specific microglia subpopulations and assessed these gene sets through re-analysis of genome wide association study (GWAS) data. The proposed additional human data collection and statistical assessments will delineate the molecular architecture of the diverse brain cell responses affected by AD and sex, and is expected to identify multiple sex-specific candidate AD risk genes. The Preliminary studies have already revealed known female-biased and novel female-specific AD risk genes, such as APOE and MERTK. We will define the sex-specific role of MERTK in the determination of AD risk and neuroinflammation using conditional mouse MERTK alleles and AD knock-in mice. In mouse models, we will define at single cell resolution the extent to which sex-specific expression responses to knock-in of FAD mutations overlap with human Late Onset AD sex-specific expression patterns, as well as sex-dependent differences in gene expression profiles responding to treatment with a synapse-preserving therapeutic. The results from our study will identify sex- specific genes and pathways for AD onset, progression, and treatment response, offering new biological insights for AD prevention and therapy.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性认知功能减退为特征的疾病， 淀粉样蛋白-β和tau聚集体。尽管是最常见的神经退行性疾病， 可用于减缓或停止AD致命性进展的治疗。三分之二的AD患者是女性， 患AD的风险更高。女性AD患者比男性有更广泛的脑组织学改变 与AD，更严重的认知症状，更严重的神经退行性变，这表明，疾病， 对女性和男性大脑的影响不同尽管AD存在明显的性别差异， 仍然知之甚少。因此，关注AD中的性别差异对于将该领域推向有效 干预措施和开发针对性别的治疗方法。 我们假设，女性和男性的大脑呈现出严重不同的疾病易感性和反应， AD病理学，特别是关于免疫结构和CNS突触可塑性。我们的初步单 尸检人类AD大脑的核RNA测序（snRNA-seq）图谱显示性别特异性 细胞组成和神经炎症特征的差异。我们确定了AD的标记基因组- 相关的女性特异性小胶质细胞亚群，并通过重新分析这些基因集， 全基因组关联研究（GWAS）数据。拟议的额外人类数据收集和统计 评估将描绘受AD影响的不同脑细胞反应的分子结构， 性别，并有望确定多个性别特异性候选AD风险基因。初步研究表明， 已经揭示了已知的女性偏见和新的女性特异性AD风险基因，如APOE和MERTK。 我们将使用以下方法确定MERTK在确定AD风险和神经炎症中的性别特异性作用： 条件性小鼠MERTK等位基因和AD敲入小鼠。在小鼠模型中，我们将以单细胞分辨率定义 对FAD突变敲入的性别特异性表达应答与人类晚期 发病AD性别特异性表达模式，以及基因表达谱的性别依赖性差异 对突触保护治疗有反应我们的研究结果将确定性别- AD发病、进展和治疗反应的特定基因和途径，提供新的生物学见解 用于AD预防和治疗。