Opposite Roles\nof Cholesterol and Lanosterol in Lipid\nMembrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation

Molecular self-assembly of amyloid-beta peptides to form\nfibrillar\naggregates is a known cause of Alzheimer’s disease. Although\nhomogeneous nucleation of amyloid-beta is unfavorable, heterogeneous\nnucleation of amyloid-beta in cell membranes plays a key role in fibril\nformation. We observed these opposite roles in the effects of cholesterol\nand lanosterol, the precursor of cholesterol in the brain, on nucleation.\nAs previously reported, cholesterol accelerated nucleation, whereas\nlanosterol decelerated it when mixed with dioleoyl-phosphatidylcholine\nat 20%. The observed opposite effects of cholesterol and lanosterol\non nucleation do not correlate with the differences in the mechanical\nand thermodynamic nature of mixed membranes. However, the affinity\nof amyloid-beta to the inner membrane seems to be related to the opposite\neffects on nucleation kinetics. Cholesterol reduced the insertion\nof amyloid-beta into the lipid membrane, whereas lanosterol promoted\nthe insertion of amyloid-beta into the membrane, which would make\namyloid-beta more tightly bound by lipid molecules and reduce its\ndiffusivity in the membrane and consequently inhibit nucleation. Our\nstudy provides insights into the effects of sterol compounds other\nthan the well-investigated cholesterol on the self-assembly of amyloid-beta\nto clarify the molecular basis underlying Alzheimer’s disease\npathology and to develop targeted therapeutic strategies.