Recent large-scale unbiased genome-wide association study (GWAS) and epidemiologic research has discovered that Alzheimer’s Disease (AD) and its related dementias (ADRD) share common risk factors associated with cardiovascular diseases. The underlying molecular and cellular factors that contribute to both ADRD and cardiovascular diseases are poorly understood. We discovered in our preliminary study that microglia-specific deletion of Mac-1 (αMβ2, CD11b/CD18 or CR3) worsens the development of ADRD, using a well-characterized 5xFAD mouse model. Our discovery contradicts a published result using a different mouse model (mThy-hAPP751) of ADRD, where the investigators reported that global deletion of Mac-1 reduces the accumulation of amyloid-β protein in the brain. The molecular mechanism underlying the opposite effects of global vs. microglia-specific deficiency of Mac-1 on amyloidosis is unknown. Mac-1 is a β2 integrin highly expressed on bone marrow-derived macrophages and resident microglia, and supports a wide range of leukocyte functions, and as such, Mac-1 is generally considered as a pro-inflammatory receptor. Unexpectedly, we discovered in 2007 that Mac-1 deficiency prevents the development of systemic immunosuppression, suggesting that Mac-1 can function as an anti-inflammatory receptor under specific settings. In support of our finding, multiple independent GWAS studies have identified a number of nonsynonymous variants of Mac-1 (R77H, A858V, P1146S) that are strongly associated with higher risks of lupus-like autoimmune diseases. In our preliminary studies, we further show that conditional inactivation of Mac-1 on resident macrophages promotes their activation, potentially by reducing the expression of the Triggering Receptor Expressed On Myeloid Cells 2 (TREM-2) protein, a cell surface receptor whose mutations are strongly associated with increased risks of ADRD in human patients as well. In this Administrative Supplement, we propose to investigate the anti-inflammatory role of microglia-expressed Mac-1 in the setting of ADRD. The central hypothesis to be tested is that microglia- specific Mac-1 protects mice against the development of ADRD by enhancing TREM-2 expression on microglia and thereby promoting their phagocytic activity toward amyloid-β. We have crossed global Mac-1−/− mice and microglia-specific Mac-1−/− (micMac-1−/−) mice with the 5xFAD mice. In Specific Aim 1, we will carefully characterize these global Mac-1−/−5xFAD vs. micMac-1−/−5xFAD mice and investigate the underlying mechanism for the opposite phenotypes, including neuroinflammation, amyloid-β deposition, and cognitive functions. In Specific Aim 2, we will investigate if Mac-1 deficiency reduces TREM-2 expression on microglia in 5xFAD mice and consequently compromises their ability to phagocytose amyloid-β in vitro and in vivo. Completion of these experiments will not only provide novel insights into the common molecular and cellular pathways that contribute to both ca...