Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments for which, currently, there is no cure. Studies in human patients and mouse models reveal disease profiles that involve the downregulation of genes involved in neural functions, such as synaptic transmission, and the upregulation of immune response and inflammatory genes. Although there are a number of neural cell types implicated in AD risk and etiology, including neurons and different types of glia, the majority of studies thus far have utilized total tissue. While these have offered great insight into AD, the establishment of techniques for analyzing cell type-specific mechanisms underlying AD etiology is critically important. In the current proposal, we will utilize a combination of molecular techniques to label and isolate populations of specific cell types, including glia and neurons, and to generate cell type-specific epigenetic and transcriptomic maps from mouse models of neurodegeneration, postmortem human brain, and human adult stem cell-derived cultures. Using integrative bioinformatic analysis, we will determine the pathways disrupted during early and late neurodegeneration. We believe these studies will provide invaluable information about the gene expression and cellular programs that mechanistically underlie AD in the human brain, and will identify novel targets for therapeutic strategies.
To begin unraveling the complexity of AD, large-scale epigenetic and transcriptomic analyses, including studies from our labs, have used unbiased genome-wide approaches to address how neurodegeneration affects chromatin states and gene expression changes, respectively. However, although there are a number of neural cell types implicated in AD risk and etiology, including neurons and different types of glia, the majority of studies thus far have utilized total tissue and likely miss crucial cell type-specific information. In the current proposal, we will generate cell type-specific epigenetic and transcriptomic maps from mouse models of neurodegeneration, postmortem human brain, and human adult stem cell-derived cultures.
| Wang, Yang; Li, Yue; Yue, Minghui et al. (2018) N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci 21:195-206 |
| Ernst, Jason; Melnikov, Alexandre; Zhang, Xiaolan et al. (2016) Genome-scale high-resolution mapping of activating and repressive nucleotides in regulatory regions. Nat Biotechnol 34:1180-1190 |
