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Objective  Microglia play a pivotal role in the initiation and progression of Alzheimer's disease ( AD ). We here tested the therapeutic hypothesis that the Ca 2+ ‐activated potassium channel  KC a3.1 constitutes a potential target for treating  AD  by reducing neuroinflammation.    Methods  To determine if  KC a3.1 is relevant to  AD , we tested if treating cultured microglia or hippocampal slices with A β  oligomer (A β O) activated  KC a3.1 in microglia, and if microglial  KC a3.1 was upregulated in 5x FAD  mice and in human  AD  brains. The expression/activity of  KC a3.1 was examined by  qPCR , Western blotting, immunohistochemistry, and whole‐cell patch‐clamp. To investigate the role of  KC a3.1 in  AD  pathology, we resynthesized senicapoc, a clinically tested  KC a3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, A β  deposition and hippocampal long‐term potentiation ( hLTP ) in 5x FAD  mice.    Results  We found markedly enhanced microglial  KC a3.1 expression/activity in brains of both 5x FAD  mice and  AD  patients. In hippocampal slices, microglial  KC a3.1 expression/activity was increased by A β O treatment, and its inhibition diminished the proinflammatory and  hLTP ‐impairing activities of A β O. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5x FAD  mice, reduced neuroinflammation, decreased cerebral amyloid load, and enhanced hippocampal neuronal plasticity.    Interpretation  Our results prompt us to propose repurposing senicapoc for  AD  clinical trials, as senicapoc has excellent pharmacological properties and was safe and well‐tolerated in a prior phase‐3 clinical trial for sickle cell anemia. Such repurposing has the potential to expedite the urgently needed new drug discovery for  AD .

Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease