title: CALHM1 ion channel elicits amyloid-β clearance by insulin-degrading enzyme in cell lines and in vivo in the mouse brain.
abstract: Alzheimer's disease is characterized by amyloid-β (Aβ) 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 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 Ca(2+) 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 strongly potentiated by CALHM1 activation. Importantly, Calhm1 knockout in mice reduced IDE enzymatic activity in the brain, and increased endogenous Aβ concentrations by up to ∼50% in both the whole brain and primary neurons. Thus, CALHM1 controls Aβ levels in cell lines and in vivo by facilitating neuronal and Ca(2+)-dependent degradation of extracellular Aβ by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in Alzheimer's disease.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Manhasset, New York 11030 USA The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Manhasset, New York 11030 USA The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chandakkar
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Manhasset, New York 11030 USA The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA.
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Blanc
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Manhasset, New York 11030 USA The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Manhasset, New York 11030 USA The Feinstein Institute for Medical Research, Manhasset, New York 11030 USA PMaramba@nshs.edu.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D018345:Mice, Knockout; D059748:Proteolysis / Q000187:drug effects; D012995:Solubility; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D016229:Amyloid beta-Peptides; C530077:CALHM1 protein, human; C575356:CALHM1 protein, mouse; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D007339:Insulysin; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D002118:Calcium
keywords: Alzheimer's disease; Amyloid-β peptide; CALHM1; Insulin-degrading enzyme; Ion channel; Secretion