title: Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer β-amyloid peptide.
abstract: Alzheimer β-amyloid (Aβ) peptides can self-organize into oligomeric ion channels with high neurotoxicity potential. Cholesterol is believed to play a key role in this process, but the molecular mechanisms linking cholesterol and amyloid channel formation have so far remained elusive. Here, we show that the short Aβ22-35 peptide, which encompasses the cholesterol-binding domain of Aβ, induces a specific increase of Ca(2+) levels in neural cells. This effect is neither observed in calcium-free medium nor in cholesterol-depleted cells, and is inhibited by zinc, a blocker of amyloid channel activity. Double mutations V24G/K28G and N27R/K28R in Aβ22-35 modify cholesterol binding and abrogate channel formation. Molecular dynamic simulations suggest that cholesterol induces a tilted α-helical topology of Aβ22-35. This facilitates the establishment of an inter-peptide hydrogen bond network involving Asn-27 and Lys-28, a key step in the octamerization of Aβ22-35 which proceeds gradually until the formation of a perfect annular channel in a phosphatidylcholine membrane. Overall, these data give mechanistic insights into the role of cholesterol in amyloid channel formation, opening up new therapeutic options for Alzheimer's disease. Aβ22-35 peptide, which encompasses the cholesterol binding domain of Aβ, induces a specific increase of Ca(2+) level in neural cells. Double mutations V24G/K28G and N27R/K28R modify cholesterol binding and abrogate channels formation. Molecular dynamic simulations suggest that cholesterol induces a tilted α-helical peptide topology facilitating the formation of annular octameric channels, as schematically shown in the graphic (with a hydrogen bond shown in green for two vicinal peptides). Overall, the data give insights into the role of cholesterol in amyloid channel formation and open up new therapeutic options for Alzheimer's disease.
authors.affiliation: Faculté des Sciences, Aix-Marseille Université, EA4674, Marseille, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Di Scala
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Troadec
authors.forename: Clément
authors.initials: C
authors.lastname: Lelièvre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Garmy
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
authors.forename: Henri
authors.initials: H
authors.lastname: Chahinian
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002784:Cholesterol
keywords: Alzheimer peptide; amyloid pore; calcium channel; neurotoxicity; oligomer