Project Summary/Abstract In 2021, an estimated 6.2 million age 65 and older individuals in the United States are living with Alzheimer’s disease (AD). In AD, aging is the leading risk factor and with increases in life expectancy, there is an urgency to better understand the overlapping or distinguishing molecular processes associated with cognitive decline in aging and AD memory impairments. As previously demonstrated by our lab and others, hippocampus-dependent learning becomes less resilient to aging and even more impaired in AD. AD has an unmet need for treatments that offset disease onset, progression or show recovery of cognitive function. One possible target for treatment development is the epigenetic machinery. The Wood lab has made significant contributions to our current understanding of the epigenome in learning and memory, such as histone acetylation/deacetylation and nucleosome remodeling in regulating gene expression required for memory consolidation. Although we know that the regulation of the epigenome is important for long-term memory formation, it is unknown how different epigenetic mechanisms are coordinated for facilitating gene expression necessary for memory consolidation. The discovery of Calcium-RESponsive Transactivator (CREST; aka SS18-like protein 1) provided a prime candidate for a transcriptional regulator with the capacity to interact with multiple epigenetic mechanisms. CREST is able to coordinate histone modification and nucleosome remodeling mechanisms using two distinct domains: the C-terminus interacts with the potent histone acetyltransferase, CBP (Creb-binding protein), whereas the N-terminus interacts with BRG1, a key enzyme of a nucleosome remodeling complex. As a potential key coordinator of major epigenetic mechanisms, CREST is also a major weak point for molecular mechanisms going awry, leading to cognitive impairment. For example, mutations in the human Crest gene have been implicated in ALS, a neurodegenerative disease, and my preliminary data shows an age-dependent decrease in CREST and that decreasing CREST expression impairs synaptic plasticity and memory. The proposed research strategy will test the hypothesis that CREST is critical for epigenetic gene regulation during memory formation in the adult brain and that its function becomes impaired with age and AD onset. The specific aims of this proposal will examine the following in the adult, aging and AD brain: Aim 1, Determine the role of CREST in hippocampal synaptic plasticity in the adult and aging brain; Aim 2, Determine the role of CREST in hippocampus-dependent memory in the adult and aging brain; Aim 3, Determine CREST-dependent gene expression and chromatin accessibility during memory consolidation in the adult and aging/AD brain. The outcome of this research will provide new innovations and insight into how we understand the regulation of memory consolidation in the adult, aging, and AD brain and outline key functional avenues to pursue for ...