Alzheimer’s disease (AD) is the most common cause of dementia and is the sixth leading cause of death in the United States. More than 5.8 million people live with AD today, and it is projected that by the year 2050, nearly 14 million people will be affected by this devastating disease. For American Indian and Alaska Native (AI/AN) communities, the effects of AD and related dementias (ADRD) will likely have an even greater impact because of the higher prevalence of risk factors associated with AD/ADRD. Indeed, the number of AI/ANs living with dementia is projected to grow over five-fold by 2060. This increase in the number of older AI/AN adults living with dementia will have a significant and detrimental impact on the vitality of whole communities. In order to address this epidemic, new therapeutics are needed that target specific pathways associated with AD/ADRD pathogenesis. For example, a significant amount of research suggests that neuroinflammation plays an active role in AD pathogenesis and that microglial cells bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell- surface formyl peptide receptor 2 (FPR2), resulting in an inflammatory response. Thus, we hypothesize that specific therapeutics that target and disrupt microglial cell activation pathways and inflammatory polarization could interrupt the harmful inflammatory events contributing to AD pathogenesis and favor a microglial M2 polarization that resolves inflammation. We propose to address this hypothesis by characterizing the human microglial inflammatory responses induced by soluble and aggregated Aβ, including intracellular Ca2+ flux, reactive oxygen species (ROS) production, cytokine/chemokine production, and nuclear factor κB (NF-κB) activation. We will also characterize microglial inflammatory phenotype switching (M1/M2) and gene expression (RNA-Seq) in response to Aβ activation. We will then evaluate effects of novel small molecule FPR2 antagonists on human microglial cell inflammatory responses to determine which compounds are effective inhibitors of inflammation and can enhance microglial M2 polarization. We have discovered a large number of FPR2 ligands over the years, including some specific for FPR2 and some with mixed receptor specificity for FPR1/FPR2, which can be biased towards FPR2. This library of FPR2 ligands will be useful for initial screening but will be followed by structure-activity relationship (SAR) analysis, molecular modeling, and acquisition/synthesis of new analogs. The accomplishment of these preclinical studies will lead to the development of a new class of prospective compounds that could be developed for the treatment of AD/ADRD, which could significantly benefit the AI/AN Communities. This is clearly an innovative approach to treating a prevalent disease where there are few effective drugs. The proposal will also address significant knowledge gaps relevant to the mechanisms of microglial inflammation induced by amyloid peptides. Further ...