Regulation of microglial lipid metabolism and immune functions by SHP-1 in Alzheimer's disease

University Of Virginia, Charlottesville VA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting millions of people in the United States; however, there is still an immense need for improved therapeutic strategies to treat or slow its progression. Increasing evidence from human AD genetic studies and experimental animal models has implicated microglia, the brain-resident macrophages, and their associated immune functions in AD pathogenesis. In particular, recent studies have linked microglial immunoreceptor tyrosine-based activating (ITAM) and inhibitory motif (ITIM) receptors, including TREM2, CD33, CD22, and SIGLEC-11, to AD risk. While spleen tyrosine kinase (SYK) is known to drive protective microglial immune functions downstream of ITAM receptors, less is known regarding the intracellular signaling molecules that orchestrate ITIM receptor-mediated coordination of microglial immune functions in AD. In the peripheral immune system, the SH2-domain-containing phosphatase (SHP)-1 (encoded by the gene Ptpn6) is known to execute immune inhibition downstream of multiple ITIM receptors and shut down the ITAM-SYK signaling axis. Despite this, the role of SHP-1 in regulating microglial biology, immune functions, and AD pathogenesis is largely unknown. To bridge this gap in knowledge and investigate how SHP-1 shapes microglial biology in response to amyloid beta (Aβ) pathology, my lab generated SHP-1fl/flCx3cr1Ert2Cre mice that harbor a conditional deletion of SHP-1 in brain macrophages and further crossed them with 5xFAD mice, a widely used model of amyloidosis (further referred to as 5xFAD SHP- 1MG mice). In my preliminary studies, I found that brain macrophage deletion of SHP-1 in 5xFAD SHP-1MG mice leads to a marked reduction Aβ plaque load, enhances microglia-plaque interactions and microglial Aβ phagocytosis, and significantly reduces microglial lipid droplet burden when compared to Cre-negative 5xFAD littermate controls. Additionally, I conducted a transcriptional analysis of isolated SHP-1-deficient brain macrophages and discovered that SHP-1 functions downstream of ITIM-containing receptors to regulate microglial activation and lipid metabolism. Given these preliminary findings as well as the emerging evidence linking lipid droplet accumulation to microglial dysfunction and AD pathogenesis, I hypothesize that SHP-1 is a central regulator of microglial lipid metabolism that functions downstream of ITIM receptors to influence Alzheimer’s-associated disease pathogenesis. In Aim 1, I will uncover which microglial ITIM-containing receptors employ SHP-1 to inhibit microglial immune functions in Aβ amyloidosis. In Aim 2, I will determine how SHP-1 orchestrates microglial lipid metabolism. Overall, the completion of the proposed studies will pioneer new insights into the role of SHP-1 in orchestrating microglial immune functions and lipid metabolism in AD-related pathogenesis. Further, this work will uncover novel microglia-specific players (i.e., SHP-1) that can be targeted to treat AD and easily translated to other neurological diseases in which microglia play critical roles.