Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. In addition to aging, sedentary behavior ranks first in the US and third in the world as a risk factor for causing cognitive decline and exacerbating AD. Greater and accelerated rates of cognitive impairment in women with AD underscore the need for identifying the mechanisms by which exercise prevents cognitive decline in normal aging and AD in both sexes. As observed by our labs and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic factor (BDNF). Our data suggest that specific exercise patterns can engage a ‘molecular memory’ for that experience that persists through periods of sedentary behavior and enables a short exercise session, to again, induce hippocampal BDNF and facilitate memory. We have proposed that epigenetic mechanisms mediate this “molecular memory” of exercise, as the epigenome represents a signal transduction platform that is capable of encoding past experience, current metabolic states (because nearly every epigenetic modification is a metabolite) and establishing stable changes in cell function that lead to long-term changes in behavior. Preliminary data in this proposal lead us to propose the novel hypothesis that specific patterns of exercise establish a molecular feedback loop that integrates rate-limiting aspects of acetyl-CoA metabolism and histone acetylation/methylation mechanisms to modulate gene expression required for long-term memory formation and synaptic plasticity. Our goal in this proposal is to define, in aging wild type and 5xFAD female and male mice, the exercise parameters that establish a molecular memory, to investigate the effect of exercise on acetyl-CoA metabolic pathways and histone modifications and to determine whether manipulations to this molecular feedback loop overcome deficiencies in synaptic plasticity and memory formation in aging and 5xFAD female and male mice. We propose three Aims. Aim 1 - Determine how specific exercise patterns affect synaptic plasticity and memory formation in aging wild type mice and 5xFAD mice. Aim 2 - determine the effect of exercise on acetyl-CoA metabolic pathways, histone modification, and gene expression in aging wild type mice and 5xFAD mice. Aim 3 - determine the effect of ameliorating hippocampal acetyl-CoA deficiencies in aging and 5xFAD mice on gene expression, synaptic plasticity and memory formation. Overall, successful completion of the research in this proposal will improve our understanding of how the epigenome integrates information from metabolism (acetyl-CoA dynamics) and experience (exercise), how this interplay becomes impaired with aging and in the context of AD, and how pharmacological modulation of acetyl-CoA dyna...