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

项目总结 阿尔茨海默病(AD)的特征是进行性认知能力下降并伴有脑积聚 淀粉样蛋白和tau聚集体。尽管是最常见的神经退行性疾病，但没有有效的 可用于延缓或阻止AD致命进展的治疗。三分之二的AD患者是女性，女性 患阿尔茨海默病的风险更高。女性阿尔茨海默病患者比男性有更广泛的脑组织学改变 与阿尔茨海默病患者相比，认知症状更严重，神经变性更严重，提示该病 对女性和男性大脑的影响不同。尽管存在明显的AD性别差异，但其机制和途径 人们对此仍然知之甚少。因此，关注阿尔茨海默病的性别差异是推动该领域走向有效的关键 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大脑对疾病的易感性和反应截然不同。 AD病理，特别是关于免疫结构和中枢神经系统突触可塑性。我们的初赛单曲 人死后阿尔茨海默病脑的核糖核酸测序(SnRNA-seq)图谱显示性别特异性 细胞组成和神经炎性特征的差异。我们确定了AD的标记基因集- 相关的女性特有的小胶质细胞亚群，并通过重新分析 全基因组联合研究(GWAS)数据。拟议增加人力数据收集和统计 评估将描绘AD和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定的候选AD风险基因。初步研究表明， 已经发现了已知的偏向女性和新的女性特有的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，我们将在单细胞分辨率下定义 对FAD基因敲入的性别特异性表达反应与人类晚期重叠的程度 阿尔茨海默病的性别特异性表达模式以及基因表达谱的性别依赖性差异 对保留突触的治疗有反应。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，提供了新的生物学见解 用于预防和治疗阿尔茨海默病。

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.