Mitochondrial DNA damages and microglia activation in Alzheimer’s disease
In aim 1, we will establish a connection between mtDNA damage in microglia and gradual Aß deposition in AD mice model (5xFAD mice) at different ages. We will also determine whether mitochondrial oxidative stress causes mtDNA damage and instability in 5xFAD microglia. In aim 2, we will define how mtDNA damage affects microglia activation in 5xFAD mice. We will explore whether mtDNA damage promotes their leakage to cytosol in 5xFAD microglia. In aim 3, we will determine the cause-and-effect relationship between mtDNA oxidative damage and inflammatory activation of microglia in 5xFAD mice.
The proposed proof-of-concept study presents a highly novel approach to address the yet not fully answered question of what mediates early microglial activation in AD. We have raised a novel concept that mtDNA oxidative damages in microglia contribute to microglial activation in AD through mtDNA leakage to cytosol. Our investigation will comprehensively examine this novel mechanism and deepen our understanding of pathogenesis of AD. If our study is complete, it will provide a new avenue for the development of therapeutic strategies by targeting mtDNA oxidative damages and leakage for AD therapy. Because similar brain pathologies occur in other neurodegenerative diseases, the findings from this study will potentially stimulate research into other neurodegenerative diseases, such as Down's syndrome and Lewy body dementia, which involve brain amyloidopathy and microglial inflammatory activation.