Dissecting the role of sex-linked genes and APOE e4 risk in AD

剖析 AD 中性相关基因和 APOE e4 风险的作用

• 批准号: 10677855
• 负责人: Christine M. Disteche
• 金额: $ 119.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677855
• 关键词: 3-Dimensional; Acceleration; Address; Age; Age Factors; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Autopsy; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Cell model; Cells; Cellular Assay; Complex; Computational Biology; Data; Dementia; Development; Disease; Disease Progression; Dose; Environmental Risk Factor; Epigenetic Process; Event; Exclusion; Female; Functional disorder; Gene Combinations; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Modified; Genes; Genetic; Genotype; Goals; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Immune; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory Response; Late Onset Alzheimer Disease; Life Style; Ligands; Link; Longevity; Metabolic Pathway; Methods; Microglia; Molecular; Myelogenous; Nerve Degeneration; Neurobiology; Neuroimmune; Neurons; Organoids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Ploidies; Predisposition; Protocols documentation; Research; Risk; Risk Factors; Role; Sex Bias; Sex Chromosomes; Sex Differences; Sex Factors; Small Nuclear RNA; Structure; Testing; Tissues; Variant; Woman; X Chromosome; X Inactivation; apolipoprotein E-4; brain cell; brain tissue; cell type; cerebral atrophy; cognitive function; cohort; data integration; disease phenotype; dosage; effective therapy; gene interaction; genetic risk factor; genetic variant; genome wide association study; genome-wide analysis; high risk; human tissue; immune function; induced pluripotent stem cell; innovation; insight; knock-down; lifetime risk; male; men; mosaic loss; neuroinflammation; neuropathology; novel; overexpression; receptor; response; sex; single nucleus RNA-sequencing; stem cell model; synergism; tool; transcriptomics; two-dimensional

Project Summary Women have a higher lifetime risk of developing Alzheimer's disease (AD) than men. This increased risk is not fully explained by differences in longevity, hormones or brain structure. Women who carry at least one copy of the APOEɛ4 allele, the strongest genetic risk factor for late onset AD (LOAD), have accelerated neuropathology. However, some studies suggest a faster decline in men, suggesting that sex bias may differ depending on the stage of the disease. Here, we will investigate how the sex chromosome complement and sex-linked genes influences sex differences in onset and progression of LOAD. Genome-wide association studies have identified genetic and epigenetic risk factors for LOAD, but the sex-chromosomes are often excluded in these studies meaning there is a lack of data on sex-linked genes. Males have unique Y-linked genes and females have higher expression of genes that escape X inactivation. Interestingly, many of the escape genes are related to immune function and neuroinflammation is a hallmark of AD, suggesting that these genes may directly contribute to disease progression. To address the impact of sex-linked genes combined with APOEɛ4 alleles on neuroinflammation in LOAD we will use unique cellular models and AD tissue for leveraging integrated omics and functional studies. We will evaluate the functional roles of sex chromosomes and sex-linked genes in brain cell types using human induced pluripotent stem cell (hiPSC) models. We have derived isogenic pairs of hiPSCs with a different number of sex chromosomes on the same genetic background (XXY/XY or XXX/X). These new hiPSC lines minimize variability between individuals, as well as environmental or hormonal confounders. We will generate isogenic pairs of these lines with ɛ3/3 or ɛ3/4 alleles by gene editing. After differentiation of hiPSC into neurons, microglia, and brain organoids we will employ a combination of `omic' analyses and functional assays focusing on neuroinflammation and neurodegeneration. This approach will identify sex-linked candidate genes, which will be tested for dosage effects by knockdown and overexpression. These in vitro studies will be validated in human tissue collected by the Precision Neuropathology Core from our Alzheimer's Disease Research Center brain bank. Using pathologically characterized AD brains we will employ myeloid-specific single-nucleus RNA sequencing to determine the effects of sex and APOEɛ4 genotypes on microglial subtypes and neuroimmune gene expression. Our new team combines expertise in hiPSC modeling, sex-linked genes, neuroinflammation, `omic analyses and neuropathology. This integrative study will help understand sex-specific genetic factors and how those factors interact with APOEɛ4 risk to modulate cellular dysfunction and pathology, thus providing novel insights into how to tailor a more effective treatment for AD.

项目总结