Characterize neuronal and glial cell-specific vulnerability to proteinopathies in Alzheimer's disease using multimodal single-nuclei genomic and epigenomic approaches

点击翻译按钮获取中文摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a devastating neurodegenerative condition that it is estimated to affect 16 million Americans by 2050. AD is mixed proteinopathies (e.g., amyloid-β (Aβ) aggregation, tau neurofibrillary tangles, and TDP-43 inclusions) and selectively affect certain regions of the brain (e.g., neocortex and hippocampus) with complex pathophysiology. and characterization of specific Although multiple studies have focused on genetic factors for AD, the delineation neuronal and glial cell populations with enriched vulnerability to proteinopathy in AD remains unknown. Our team has demonstrated that single-cell/nucleus multi-omics (snRNA-seq/snATAC- seq) can be used to investigate both “normal” and “pathological” neuronal and glial subpopulations from human post-mortem brains and we have also established a large human brain biobank with diverse proteinopathies (including Aβ, tau, TDP-43 and others). Moreover, we have demonstrated how targeting proteinopathy-specific networks, such as acetylated Tau and synergistic proteinopathy networks shared by Tau and Aβ, can identify repurposable treatments (e.g., sildenafil and diflunisal) for AD. Our preliminary snRNA-seq and snATACT-seq analyses of human post-mortem cerebellum regions from 7 individuals (n=4 [AD] and n=3 other dementia cases) have revealed unique neuronal and glial cell populations and genes/networks when comparing to traditional snRNA-seq data from neocortex and hippocampus. Our integrative snRNA-seq data analysis has also identified disease-relevant microglial subtypes, including microglia containing amyloid-b/phosphor-tau, as well as microglia enriched in expression of pro-inflammatory markers, using deep generative models. We therefore hypothesize that comprehensive characterization of human neuronal and glial cell genomic and epigenomic signatures and networks that are vulnerable to proteinopathies will help to identify novel mechanistic pathways and disease- modifying treatments. In Aim 1, we will generate comprehensive multi-ome data of human neuronal and glial cells vulnerable to AD proteinopathies. We will use a sample pooling snRNA-seq/snATAC-seq technology to analyze human post-mortem neocortex, hippocampus, and cerebellum with varying degrees of proteinopathy severity (amyloid-b, p-tau and TDP-43) and age-, sex- and APOE-matched cognitive healthy controls available from the Northwestern Alzheimer’s Disease Research Center. In Aim 2, we will test the hypothesis that neuronal and/or glial cell-specific genomic/epigenomic signatures and networks identify the molecular mechanism(s) of vulnerability and resilience in AD. These multimodal data analyses will integrate large snRNA-seq/snATAC-seq profiles with existing whole genome-sequencing data from the Alzheimer’s disease sequencing project (ADSP). In Aim 3, we will test the hypothesis that selective cellular vulnerability linked to genes/networks can be targeted via pharmacologic treatment to slow progression of AD-like disease in animal models. Successful completion of our project will identify new treatment opportunities that target specific neuronal and/or glial cell-specific risk/resilience genes and networks that confer vulnerability to proteinopathies in AD and other dementias.