Impact of phagocytosis on amyloid beta-induced pathology

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IMPACT OF PHAGOCYTOSIS ON AMYLOID BETA-INDUCED PATHOLOGY Abstract Alzheimer's disease (AD) is a devastating neurodegenerative disease that impacts more than 6 million Americans and millions more Worldwide. Despite years of active research, our understanding of this disease is incomplete, and the patient population remains without effective therapeutic options. In AD, clearance of apoptotic neurons and amyloid-beta aggregates is reduced, as microglia become overloaded with chronically phagocytosed debris. The current dogma suggests that decreased clearance of apoptotic cells, also known as “efferocytosis”, inevitably leads to pathology. However, our preliminary data suggest that this concept warrants further testing. We show here that pharmacologic or genetic efferocytosis reduction (not complete ablation) can reduce inflammation in mouse models of inflammatory arthritis and kidney injury, suggesting unexpected benefits of reduced clearance in inflammation. In this proposal, we will test the hypothesis that reduced efferocytosis alleviates amyloid-beta induced pathology through enhanced debris processing/degradation (due to reduced load of phagocytes such as microglia). We will pursue the following aims: 1. Using mice with genetic decrease in efferocytosis due to the combined loss of four different efferocytosis receptors, we will test debris (apoptotic cells, amyloid-beta aggregates, myelin debris) clearance, processing, and response of microglia ex vivo. 2. By crossing these mice with the mouse model of amyloid-beta induced pathology and Alzheimer's disease (5xFAD mice), we will quantify multiple disease parameters, determine the numbers of apoptotic cells in the brain, and analyze the microglial response in the reduced clearance environment in vivo. Our proposal is innovative because we will challenge the dogma that reduced efferocytosis is universally detrimental. Our proposal is significant because these studies will provide new knowledge to the community about the contribution of efferocytosis to AD pathology and provide new avenues to therapy in AD.