Alzheimer's disease (AD) is a devastating neurodegenerative disorder that still lacks effective early-detection and treatment options. The pre-clinical phase of AD, when amyloid pathology starts before onset of cognitive impairment, is a unique window of opportunity for detection and intervention, to prevent or delay progression of neurodegeneration. Epigenetic dysregulation is association with AD in both human patients and animal models. However, the epigenetic changes arising during the pre-clinical stages of AD are still unknown, hindering the design of effective early biomarkers and therapies for AD. This is largely due to research focus on post-mortem human tissue, which often present advance disease manifestation and are confounded by effects of aging. Our ultimate goal is to identify early markers of epigenetics dysregulation and find targets for epigenetic therapy, in order to slow down or block A? deposition, before the other clinical symptoms of AD appear. The first step towards this goal is to comprehensively characterize early epigenetic and gene expression changes in the AD brain, in the absence of confounding effects, such as aging. Here we propose to use human amyloid precursor protein (APP) replacement knock-in (KI) mice or APPNL-G-F, a novel model in which A? accumulation starts at 8 weeks, while memory impairment does not manifest until 24 weeks. This model overproduces pathogenic A? without overexpressing the human APP or other genes. As the timing of A? deposition and AD onset are known in APPNL-G- F, we will be able to characterize epigenetic and gene expression differences between APPNL-G- F and age-matched wild type (wt) littermates precisely during the pre-clinical stage.
In Aim 1, we will compare DNA methylation (5mC), DNA hydroxymethylation (5mhC), enhancer-related histone modifications (H3K4me1, H3K4me3, and H3K27ac), and gene expression in the hippocampal (HP) neurons of wild type (C57BL/6J) and APPNL-G-F mice, at three time points: 3 weeks (baseline), 8 weeks (A? deposition without memory impairment, mimicking start of preclinical AD), and 24 weeks (AD onset). Comparison of genotypes across time-points will allow us to identify: 1) differentially hydroxyl/methylated genomic regions (DMRs/DhMRs), 2) differentially activated enhancers, and 3) differentially expressed genes, before and after AD onset in young mice. In order to translate findings to human, we will identify human orthologs of all AD-related mouse DMR/DhMRs, enhancers and genes, and compare them to publicly available human data. Finally, to develop candidate biomarkers, we will identify DMRs in blood of the same mice used in Aim 1 and determine which are shared or associated with hippocampal DMRs. Through the integration of different omics dataset, this study will provide a comprehensive view of the early epigenetic mechanisms underlying AD, advancing our knowledge about the pre-clinical stage of AD, when intervention would be more effective.
Alzheimer's disease (AD) is the sixth leading cause of death in the United States and the most common cause of dementia in older adults. The proposed project is relevant to public health because it investigates altered epigenetics regulation in AD with the goal of designing appropriate therapies in the pre-clinical phases of this terrible disease. The proposed research is relevant to the NIH's mission of increasing knowledge in order to reduce human disability.
