ABSTRACT
Genome-wide association studies (GWAS) have identified many gene polymorphisms associated with an increased risk of developing Late Onset Alzheimer's Disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing microglia innate immune responses and lipid metabolism. Angiotensin Converting Enzyme (ACE), a GWAS LOAD risk-associated gene best known for its role in regulating systemic blood pressure, also enhances innate immunity and lipid processing in peripheral myeloid cells, but a role for ACE in modulating the function of myeloid-derived microglia remains unexplored. Using novel mice engineered to express ACE in microglia and CNS associated macrophages (CAMs), we find that ACE expression in microglia reduces Aß plaque load, preserves vulnerable neurons and excitatory synapses, and greatly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of Alzheimer's Disease (AD). ACE-expressing microglia show enhanced Aß phagocytosis and endolysosomal trafficking, increased clustering around amyloid plaques, and increased SYK tyrosine kinase activation downstream of the major Aß receptors, TREM2 and CLEC7A. Single microglia sequencing and digital spatial profiling identifies downstream SYK signaling modules that are expressed by ACE expression in microglia that mediate endolysosomal biogenesis and trafficking, mTOR and PI3K/AKT signaling, and increased oxidative phosphorylation, while gene silencing or pharmacologic inhibition of SYK activity in ACE-expressing microglia abrogates the potentiated Aß engulfment and endolysosomal trafficking. These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing microglia as a cell-based therapy to augment endogenous microglial responses to Aß in AD.
