FOXO3 dependent proinflammatory transcription program of AD

PROJECT SUMMARY The overall goal of the current project is to determine the functional significance of microglial FOXO3 in Alzheimer’s disease (AD). AD is the leading cause of dementia in the elderly. In addition to the hallmark pathological features, such as β-amyloid peptide (Aβ) plaques, tangles and widespread neuronal loss, there are profound inflammatory changes in the AD brain. Microglia, the brain's immune cell, links closely to all pathological cascades including amyloid, tau and neuroinflammatory changes. Genome-wide association studies (GWAS) have revealed that the known AD risk genes are predominantly expressed in microglia, including the genes encoding the triggering receptor expressed on myeloid cells-2 (TREM2). Aberrant elevation of type-I interferon (IFN-I) signaling, typically associated with an antiviral immune response, has been observed in AD. Recent studies have identified a microglial IFN-I signature in the aging brain as well as in AD, suggesting a role for IFN-I signaling in AD pathobiology. We recently demonstrated that the FOXO3 gene, encoding the transcription factor forkhead box O-3, is a key mediator of cellular stress-induced IFN-I response. FOXO3 is one of the strongest genetic modifiers that determines the longevity of humans as well as a critical regulator of aging process. It is highly expressed in the brain with its abundance in microglia. Our preliminary data shows that FOXO3 signaling is critical for the regulation of lipid droplet accumulation as well as IFN-I pathway activation in microglial cells. Furthermore, FOXO3 directly mediates the signal from TREM2, a prime regulator of microglial activities, making it an attractive molecular target for therapeutic intervention in AD. Despite its critical role in IFN-I response and aging, the role of microglial FOXO3 in AD pathobiology remains elusive. Our central hypothesis is that aberrantly activated FOXO3 critically contributed to microglial activation states, including disease-associated microglia (DAM). To this end, our Specific Aims are: To determine the role for microglial FOXO3 in AD-associated phenotypes in a transgenic mouse model of AD; To investigate the role for FOXO3 in microglial functions in human iPSC-derived microglia (iMGL) model. The proposed study will demonstrate the role of microglial FOXO3 in AD pathogenesis and lay the foundation for therapeutic strategies to restore normal microglia function.