Thameem Dheen, Ph.D., and Jai S. Polepalli, M.A.S., Ph.D, National University of Singapore
Competition Sponsor: Ministry of Health and National Research Foundation of Singapore
With a rapidly aging population, an increase in frequency of individuals with cognitive dysfunction and progressive deterioration of memory, represent an enormous socio-economic burden. Recent studies show that microglia, the resident immune cell of the brain, express memory molecules which are involved in synaptic plasticity in the healthy brain. During aging, microglia become dystrophic and may show a reduction in their ability to maintain synaptic functions, thereby resulting in cognitive decline. Given the plasticity of microglial cells in the CNS, we hypothesize that microglia, which have been shown to be involved in learning and memory, can be targeted to complement and enhance neuronal functions by providing memory molecules in the aging brain.
To address this hypothesis, we will employ a combination of cutting-edge techniques for morphological (in vivo imaging using 2 photon microscopy and histology), molecular, epigenetic and functional (electrophysiology) analyses to investigate 2 overarching objectives. Firstly, we will characterize microglia in healthy aging brain using single cell RNA sequencing, histone profiling, and morphological analysis using multiphoton microscopy techniques to understand the molecular and epigenetic profile of dystrophic microglia. Further, we aim to develop in vitro models of aging microglia to perform functional analysis of the dystrophy associated genes. Secondly, we propose to explore how dystrophic microglia influence cognitive functions using electrophysiology studies in the aging rat brain, and to evaluate if these cognitive functions can be improved by administration of epidrugs such as HDAC inhibitors. A key outcome of this proposal is a comprehensive understanding of dystrophic microglia in the aging brain which will form the basis for microglia-centric therapies (epidrugs) to improve microglial functions and subsequently delay cognitive decline in the aging brain.
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