Cholesterol inhibits the insertion of the Alzheimer's peptide Aβ(25-35) in lipid bilayers

The physiological relationship between brain cholesterol content and the action of amyloid beta (A beta) peptide in Alzheimer's disease (AD) is a highly controversially discussed topic. Evidences for modulations of the A beta/membrane interaction induced by plasma membrane cholesterol have already been observed. We have recently reported that A beta(25-35) is capable of inserting in lipid membranes and perturbing their structure. Applying neutron diffraction and selective deuteration, we now demonstrate that cholesterol alters, at the molecular level, the capability of A beta(25-35) to penetrate into the lipid bilayers; in particular, a molar weight content of 20% of cholesterol hinders the intercalation of monomeric A beta(25-35) completely. At very low cholesterol content (about 1% molar weight) the location of the C-terminal part of A beta(25-35) has been unequivocally established in the hydrocarbon region of the membrane, in agreement with our previous results on pure phospholipids membrane. These results link a structural property to a physiological and functional behavior and point to a therapeutical approach to prevent the AD by modulation of membrane properties.