Wednesday, February 5, 2025
2/5/2025
ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and neuropathological changes in the brain. Aging remains the single largest risk factor for sporadic AD, but the mechanisms underlying this risk are not well understood. Epigenetics has been implicated in both aging and the pathogenesis of AD. Promising results from our group and others have showed that epigenetic alterations occur during aging and thereby affect neuronal function, as well as contributing to memory deficits and the pathogenesis of AD. In the proposed project, we will use mouse models of both aging and AD, as well as human postmortem tissues, to determine the histone modifications in the epigenome that occur during aging. We will also determine whether these changes promote the development of neuropathological changes that are associated with AD. Our hypothesis is that dysregulations of histone modification during aging promote AD by initiating the development of AD-related changes in neuronal networks at the molecular level. In turn, we also hypothesize that histonedeacetylase (HDAC) inhibitorscan mitigate or even prevent the neuropathogenesis of AD. To test our hypotheses, we will first map histone modifications that occur at three critical life stages (3, 12 and 18 months of age) in both wild-type (WT) and APP/PS1 mice, as well as human postmortem tissues (AD patients, young, aged healthy controls), to determine whether differential histone acetylation and methylation contribute to memory deficits and neuropathological changes associated with AD. This will be achieved through CUT&RUN seq and RNA seq combined with pathway analysis to determine the functional consequence of significant genes that are regulated by epigenetics. We will also profile histone modifications at specific gene promoter regions that are related to memory, synaptic plasticity, and the typical elements of AD neuropathology. Second, given that HDACs are key factors in histone modification and in the regulation of gene transcription, we will determine whether dysfunction of any specific HDACs causes memory deficits in AD mouse models. For this purpose, we will utilize genetic editing tools including CRISPR/Cas9-mediated knock-down and AAV9-eGFP- mediated over-expression to identify critical HDACs (eg. HDAC2 and 3) that modulate histone acetylation and methylation marks at gene promoters specifically linked to memory and neuronal plasticity. Finally, we will determine whether HDAC inhibitors have beneficial effects on memory-like behaviors and AD-like neuropathological changes in APP/PS1 mice (3, 12 and 18 months of age) as well as in age-matched WT mice. More specifically, we will investigate whether non-selective (i.e., VPA) or selective HDAC inhibitors (i.e., MS-275 and CI-994) are effective in preventing and/or rescuing memory function and neuronal changes in aging and AD mouse models. Overall, this project will significantly improve our understanding of the epigenetic mechanisms that link aging with the neuropathogenesis of AD. Identification of these mechanisms will lay the basis for developing novel therapeutic strategies for the prevention and treatment of AD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).