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

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-activated potassium channel KCa3.1 constitutes a potential target for treating AD by reducing neuroinflammation.

Methods: To determine if KCa3.1 is relevant to AD, we tested if treating cultured microglia or hippocampal slices with A oligomer (AO) activated KCa3.1 in microglia, and if microglial KCa3.1 was upregulated in 5xFAD mice and in human AD brains. The expression/activity of KCa3.1 was examined by qPCR, Western blotting, immunohistochemistry, and whole-cell patch-clamp. To investigate the role of KCa3.1 in AD pathology, we resynthesized senicapoc, a clinically tested KCa3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, A deposition and hippocampal long-term potentiation (hLTP) in 5xFAD mice.

Results: We found markedly enhanced microglial KCa3.1 expression/activity in brains of both 5xFAD mice and AD patients. In hippocampal slices, microglial KCa3.1 expression/activity was increased by AO treatment, and its inhibition diminished the proinflammatory and hLTP-impairing activities of AO. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5xFAD 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.