PROJECT SUMMARY The funded award (R01NS112516) focuses on the role of alarmins in activating innate immune responses in the brain. My laboratory has studied the role of two alarmins, IL-1a and IL-33, that independently trigger inflammation and protective immunity against a brain infection. Interestingly, IL-1a and IL-33, share a co- receptor, interleukin-1 receptor accessory protein (IL-1RAP). Of relevance to Alzheimer’s Disease (AD) and the basis of this administrative supplement application, SNPs in il1rap have been associated with AD progression, the accumulation of amyloid plaques, and decreased inflammation in the brain. These findings also implicate the role for alarmins that bind and signal through IL-1RAP (IL-1, IL-33, and the lesser studied IL-36 family members), molecules expressed in healthy cells that are released upon cell death and initiate local inflammation. Of note, genome-wide association studies have also implicated SNPs in il1a and il33 in AD, but to a lesser degree. Taken together, several human genetic studies have implicated aberrant alarmin sensing in the progression of AD. My laboratory has been studying the expression, sensing, and importance of alarmins in the brain for several years. We have an extensive understanding of how these molecules promote immunity to infection and have unique tools to understand alarmin biology in AD. Importantly, we find that alarmins activate the brain to promote the entry of peripheral immune cells to the CNS during infection, especially phagocytic monocyte-derived macrophages. We hypothesize that alarmin signaling is necessary to facilitate enhanced phagocytosis in the AD brain. To test this hypothesis, we propose three aims that mirror those of the funded application.