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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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.

项目总结