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.