Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by neuroinflammation associated with amyloid plaques and tau-containing neurofibrillary tangles. Despite extensive research, few disease-modifying therapies are available. The relatively small clinical benefits and the safety concerns of the recently approved anti-amyloid therapeutics necessitate the identification of novel therapeutic targets. Research in our lab has revealed that an enzyme (termed Ch25h) that chemically modifies cholesterol is produced in the brain’s immune cells called microglia when they are activated in a mouse model of tauopathy. Interestingly, when Ch25h is eliminated by gene deletion in the mouse model of tauopathy, neuroinflammation as well as neurodegeneration is dramatically reduced. Given these results, we hypothesize that inhibiting Ch25h with small molecule inhibitors also may mitigate neuroinflammation and neurodegeneration in the tauopathy mouse model. In this proposal, we aim to identify small molecule inhibitors of Ch25h using state-of-the-art computational and medicinal chemistry approaches. The best compounds will be tested for efficacy in the mouse model of tauopathy. If successful, these small molecule inhibitors will form a new class of drugs to target neuroinflammation and neurodegeneration in AD and related dementias.