Project Summary Extensive evidence suggests that dysregulation of innate immunity plays a key role in AD pathogenesis. It has been increasingly acknowledged that tightly regulated stimulation of innate immunity processes and specific microglia/macrophage activation can be neuroprotective depending on the stimulus and the environment. Toll- like receptors (TLRs) are a family of innate immune regulators known to play an important role in governing the phenotypic status of microglia. Major drawbacks of current immunotherapeutic approaches, including the recently FDA-approved aducanumab, are limited effectiveness against CAA and increased incidence of CAA- linked complications, such as amyloid-related imaging abnormalities (ARIA). CAA, for which there is no treatment, is present in nearly all AD cases and promotes rapid cognitive decline. Our initial data using a more proximate non-human primate (NHP) model of sporadic AD amyloid pathology, squirrel monkey (SQM), which develops abundant CAA in all aged animals (unlike other primates), indicates that treatment with CpG ODN Class C safely ameliorates CAA while promoting cognitive benefits. This proposal tackles a new perspective of innate immunity of Natural Killer T (NKT) cells in squirrel monkey. This project is significant because it is the first in the field to study the mechanism of NKT cell mediated activation of innate immune cells in squirrel monkey. Proposed studies will investigate the molecular mechanisms of delivery the synthetic lipid α-GalCer to activation of NKT leading progressively enhancing innate/adaptive immune responses in cytokines production and DC activation. Data generated from the proposed studies in squirrel monkey model will form the basis for designing molecular mechanism-driven innovative strategies to garner the adjuvant potential of NKT cells approaches with clinical utility to Alzheimer’s disease (AD). The successful completion of this project will enable us to test the novel concept of immunomodulation in primate models, a critical step before studies in human clinical trials.