J Cell Sci
Alzheimer's disease is characterized by amyloid-beta (Abeta) peptide accumulation in the brain. CALHM1, a cell-surface Ca(2+) channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls Abeta levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Abeta clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca(2+) were required for the Abeta-lowering effect of CALHM1. Abeta level reduction by CALHM1 could be explained by an increase in extracellular Abeta 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 Abeta concentrations by up to approximately 50% in both the whole brain and primary neurons. Thus, CALHM1 controls Abeta levels in cell lines and in vivo by facilitating neuronal and Ca(2+)-dependent degradation of extracellular Abeta by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in Alzheimer's disease.
Faculty; Northwell Researcher
School of Medicine; Northwell Health