CD36 SCAVENGER RECEPTOR PROMOTES ADAPTIVE T-CELL CNS INFILTRATION AND NEUROINFLAMMATION IN APPSAA KNOCK-IN MOUSE MODEL OF ALZHEIMER'S DISEASE

CD36 is a type B scavenger membrane protein with wide distribution in the body. These receptors are commonly expressed by myeloid cells, such as macrophages, microglia, and endothelial cells, which function in the cellular uptake of long-chain fatty acids and oxidized low density lipoproteins. In Alzheimer’s Disease (AD), the CD36 scavenger receptor is one of the receptors for hydrophobic amyloid beta (Aβ) fibrils, and its role is not fully understood. Neuroinflammation plays an important role in AD development and progression. Microglial activation has been shown to promote the CNS infiltration of immune cells, including CD4+ and CD8+ T cells, that exacerbate neuroinflammation and lead to the loss of synaptic-associated proteins and, ultimately, neuronal damage. Studies have shown that neuroinflammation correlates with AD pathology, which comprises Aβ accumulation, tau phosphorylation, and cognitive decline associated with synaptic and neuronal loss. Here, we aim to elucidate the role of the CD36 receptor in neuroinflammation in AD using a novel AppSAA knock-in AD model. Our central hypothesis is that deleting the CD36 receptor will improve AD pathology by attenuating neuroinflammation and microglia activation and reducing immune cell infiltration into the brains of AD animals. To test our hypothesis, we crossed AppSAA knock-in mice with CD36KO mice to generate CD36KOAppSAA mice, while AppSAA mice served as control animals. We observed decreased Aβ plaques in CD36KOAppSAA mice compared to AppSAA mice. Analyzing microglial phenotypes, we found microglia from CD36KOAppSAA mice exhibited an enhanced phagocytic marker, Clec7a. In addition, the single-cell RNA sequencing results revealed increased numbers of disease-associated microglia (DAM), which play an essential role in the phagocytosis of Aβ plaques, in CD36KOAppSAA mice compared to AppSAA mice. Furthermore, we observed a trend of reduced microglial activation and suppressed inflammatory cytokine expression in CD36KOAppSAA mice compared to AppSAA mice. Finally, our results showed attenuated infiltrating T cells in the brains of CD36KOAppSAA mice compared to those of AppSAA mice. Altogether, our findings suggest that the CD36 receptor activation may promote microglial activation and neuroinflammation that subsequently recruit infiltrating T cells into the CNS, leading to exacerbated Aβ pathology in AD. Hence, targeting the CD36 receptor may represent a novel strategy for modulating neuroinflammation and Aβ pathology in AD.