IGF2 regulation of microglia and synaptic function during aging

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Project Summary/Abstract The aging process is characterized by deficits in learning and memory and a general decline in cognitive abilities, which affects nearly 33% of U.S. adults over the age of 70. The emotional and financial burden of the aging process on caregivers, family, and taxpayers is substantial, as the projected percentage of the population will increase from 4.1% to approximately 20% by 2050 for individuals 65 and older. A thorough understanding of the processes that go awry during aging will not only provide a mechanistic understanding of aging, but will also provide key avenues for ongoing research to minimize the negative effects of the aging process on memory. The debilitating effects of aging have been linked to several neurological processes that change prior to substantial tissue deterioration and behavioral effects observed in older populations. Notably, alterations in neuroinflammation and synaptic plasticity have been independently studied and change with age in the hippocampus, a major brain region involved in the formation and storage of most memories. Activity of microglia regulate neuroinflammatory responses, which has been linked to decreased neuronal integrity, and as neuronal integrity decreases, deficits in synaptic strength and learning and memory have been reported. However, a link between neuroinflammation, studied with microglia activation, and age-related deficits in synaptic plasticity and memory are currently unclear. Insulin like growth factor 2 (Igf2) is a protein encoding gene that regulates neuroinflammation, synaptic plasticity, and memory formation. Interestingly, increased DNA methylation of Igf2 occurs over the course of the lifespan, which leads to decreased Igf2 expression. This coincides with age-related deficits in synaptic plasticity and memory formation, and increases in inflammatory responses. However, whether increased Igf2 DNA methylation leads to age-related increases in neuroinflammation and decreases in synaptic plasticity and memory remain equivocal. The goal of this proposal is to provide direct evidence linking Igf2 DNA methylation to increased neuroinflammatory responses and deficits in synaptic plasticity and memory during the aging process. We will test this in two aims by bidirectionally manipulating Igf2 DNA methylation in the hippocampus using a modified version of the CRISPR-dCas9 system. Aim 1 will determine the impact of Igf2 methylation on neuroinflammation, using common markers of microglia activation and synaptic plasticity. Aim 2 will bidirectionally manipulate Igf2 methylation to understand the effects on learning and memory in aged animals using several hippocampal dependent memory tasks. Collectively, these results will provide insight for a mechanism through which changes in Igf2 expression via altered DNA methylation influence neuroinflammatory responses and age-related deficits in synaptic plasticity and memory formation.