Novel Roles of P2RY12 in Regulating Microglial States and Early Neurodegeneration in 5xFAD Mice 72 views

Microglia are central regulators of brain homeostasis and inflammation. Their ability to balance metabolic activity and immune signaling determines how the central nervous system responds to injury and disease. Among microglial signature receptors, P2RY12 is a purinergic G-protein–coupled receptor that maintains microglial homeostasis but becomes downregulated in disease-associated microglia. The mechanisms through which P2RY12 influences microglial metabolic programming and vulnerability to neurodegeneration remain poorly understood. This dissertation investigates how P2RY12 regulates microglial metabolic, antioxidant, and immune functions under both physiological and pathological contexts. Chapter II (published in Glia, 2025) demonstrates that loss of P2RY12 shifts microglia toward a hypermetabolic transcriptional state, disrupts antioxidant pathways involving the GPX4–glutathione axis, and enhances susceptibility to ferroptotic stress. Chapter III extends these findings to an in vivo model of early Alzheimer’s disease (P2RY12KO–5xFAD mice), revealing that P2RY12 deficiency increases amyloid burden and accelerates cortical plaque deposition at 2 months of age—an early and critical stage in disease progression. Together, these studies identify P2RY12 as a molecular checkpoint for microglial metabolic resilience, linking its loss to oxidative stress and early neurodegenerative changes. The appendices include supporting data on astrocytic adaptations in P2RY12-deficient mice and undergraduate research demonstrating microglial regulation of myelin maintenance.

PHD (Doctor of Philosophy)

P2RY12, Microglia, Metabolic reprogramming, Ferroptosis, Alzheimer’s disease, Oxidative stress, Amyloid-β

This work was supported by the NIH (NS119243, NS122782), the Owen’s Family Foundation, and the iPRIME Fellowship (891902342)

English

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2026-04-28