Epigenetic regulation and function of microglia subsets in aging white matter
Description: Vascular dementia (VaD) is a prevalent cause of adult disability, but there is no treatment to combat this devastating disease. A consistent hallmark of VaD is white matter degeneration, which precedes symptom onset and correlates with the severity of cognitive decline. However, the mechanisms that lead to progressive white matter pathology in VaD and other age-related dementias remain poorly understood. Recently, human genetics studies have linked mutations in microglial genes to white matter disorders associated with cognitive impairment and dementia, suggesting a role for microglia in driving pathology. In line with this, a reactive subset of microglia that upregulates the VaD risk gene APOE appears in aging white matter. What regulates the emergence of these reactive white matter-associated microglia (WAM), and how do WAM contribute to age-related white matter degeneration and associated dementias? As particularly long-lived cells within the brain, microglia function in adulthood and old age may be shaped by immune challenges earlier in life. This proposal tests the innovative hypothesis that developmental activation of white matter microglia subsets primes them for conversion to WAM in old age, where they serve protective, APOE-dependent functions. Using novel transgenic mice and cutting-edge genomic technologies, I will perform lineage tracing, epigenetic profiling, and cell-specific ablation/gene knockouts to define cellular and molecular mechanisms regulating the emergence and functions of WAM. These studies will yield mechanistic insights into subpopulations of microglia that may contribute to age-related white matter diseases like VaD, providing a foundation for developing microglia-based interventions to combat disease progression and improve patient lives.
Funder: American Heart Association
Amount: $65,110
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2023-01-01
End date: 2024-12-31
Investigators: Nora Abduljawad, Nora Abduljawad
Institution: Washington University in St.Louis
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 4
Funder award ID: 23PRE1025832
OpenAlex ID: G3472301176