Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) 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 Aβ levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Aβ clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca2+ were required for the Aβ lowering effect of CALHM1. Aβ level reduction by CALHM1 could be explained by an increase in extracellular Aβ degradation by insulin-degrading enzyme (IDE), extracellular secretion of which was robustly potentiated by CALHM1 activation. Importantly, Calhm1 knockout in mice reduced IDE enzymatic activity in the brain, and increased up to ∼50% endogenous Aβ concentrations in both the whole brain and primary neurons. Thus, CALHM1 controls Aβ levels in cell lines and in vivo by facilitating neuronal and Ca2+-dependent degradation of extracellular Aβ by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in AD.
- © 2015. Published by The Company of Biologists Ltd