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Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain

研究成人、衰老和 AD 大脑中记忆形成的表观遗传学和代谢界面

基本信息

批准号：
10420533
负责人：
Carl Wayne Cotman
金额：
$ 66.6万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10420533
关键词：
ATAC-seq Acetyl Coenzyme A Acetyl-CoA Carboxylase Acetylation Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease risk Behavior Brain Brain-Derived Neurotrophic Factor Cell Culture Techniques Cell Nucleus Cell physiology Censuses Chromatin Cognition Cognitive Data Enzymes Epigenetic Process Equilibrium Exercise Feedback Female Foundations Frequencies Future Gene Expression Gene Expression Regulation Goals Health Hippocampus (Brain)Histone Acetylation Histone H3 Impaired cognition Impairment Individual Intervention Lead Learning Long-Term Potentiation Longevity Lysine Measures Mediating Memory Metabolic Metabolic Pathway Metabolism Methylation Modeling Modification Molecular Mus Neurons Pathway interactions Pattern Pharmacology Population Regulation Reporting Research Risk Factors Signal Transduction Synaptic Transmission Synaptic plasticity Therapeutic Time United States Update Wild Type Mouse Woman Work age related aged aging brain aging hippocampus brain health design epigenetic regulation epigenome experience gene repression histone modification improved insight long term memory male memory consolidation memory process modifiable risk mouse model normal aging novel novel strategies prevent sedentary lifestyle sex spatial memory therapeutic development transcriptome sequencing

项目摘要

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 dynamics may improve age- and AD-related cognitive dysfunction.

项目总结/文摘