CALHM1 ion channel elicits amyloid-β clearance by insulin-degrading enzyme in cell lines and in vivo in the mouse brain

Alzheimer's disease is characterized by amyloid-beta (A beta) peptide accumulation in the brain. CALHM1, a cell-surface Ca2+ channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls A beta levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of A beta clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca2+ were required for the A beta-lowering effect of CALHM1. A beta level reduction by CALHM1 could be explained by an increase in extracellular A beta degradation by insulin-degrading enzyme (IDE), extracellular secretion of which was strongly potentiated by CALHM1 activation. Importantly, Calhm1 knockout in mice reduced IDE enzymatic activity in the brain, and increased endogenous A beta concentrations by up to similar to 50% in both the whole brain and primary neurons. Thus, CALHM1 controls A beta levels in cell lines and in vivo by facilitating neuronal and Ca2+-dependent degradation of extracellular A beta by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in Alzheimer's disease.