Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer beta-amyloid peptide

作者：Di Scala Coralie; Troadec Jean Denis; Lelievre Clement; Garmy Nicolas; Fantini Jacques; Chahinian Henri^*

来源：Journal of Neurochemistry, 2014, 128(1): 186-195.

DOI：10.1111/jnc.12390

• Alzheimer peptide
• amyloid pore
• calcium channel
• neurotoxicity
• oligomer

Alzheimer beta-amyloid (A beta) 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 A beta 22-35 peptide, which encompasses the cholesterol-binding domain of A beta, 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 A beta 22-35 modify cholesterol binding and abrogate channel formation. Molecular dynamic simulations suggest that cholesterol induces a tilted alpha-helical topology of A beta 22-35. This facilitates the establishment of an inter-peptide hydrogen bond network involving Asn-27 and Lys-28, a key step in the octamerization of A beta 22-35 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.

• 出版日期2014-1