Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer β-amyloid peptide
Article first published online: 28 AUG 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 128, Issue 1, pages 186–195, January 2014
How to Cite
J. Neurochem. (2014) 128, 186–195.
- Issue published online: 17 DEC 2013
- Article first published online: 28 AUG 2013
- Accepted manuscript online: 6 AUG 2013 08:56PM EST
- Manuscript Accepted: 31 JUL 2013
- Manuscript Revised: 22 JUL 2013
- Manuscript Received: 4 JUL 2013
- Alzheimer peptide;
- amyloid pore;
- calcium channel;
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 Ca2+ 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 Ca2+ 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.