Interaction of Alzheimer's β-Amyloid Peptides with Cholesterol: Mechanistic Insights into Amyloid Pore Formation

Brain cholesterol plays a critical role in Alzheimer's disease and other neurodegenerative diseases. The molecular mechanisms linking cholesterol to neurotoxicity have remained elusive for a long time, but recent data have allowed the identification of functional cholesterol-binding domains in several amyloidogenic proteins involved in neurodegenerative diseases, including Alzheimer's disease. In this review, we analyze the cholesterol binding properties of beta-amyloid (4) peptides and the impact of these interactions on amyloid pore formation. We show that although the cholesterol-binding domains of A beta peptides and of transmembrane precursor C99 are partially overlapping, they involve distinct amino acid residues, so that cholesterol has a greater affinity for than for C99. Synthetic 22-35 and 25-35 fragments of A beta retained the ability of the full-length peptide 1-42 to bind cholesterol and to form zinc-sensitive, calcium-permeable amyloid pores in cultured neural cells. Studies with mutant peptides allowed the identification of key residues involved in cholesterol binding and channel formation. Cholesterol promoted the insertion of A beta in the plasma membrane, induced alpha-helical structuration, and forced the peptide to adopt a tilted topology that favored the oligomerization process. Bexarotene, an amphipathic drug currently considered as a potential candidate medication for the treatment of neurodegenerative diseases, competed with cholesterol for binding to A beta and prevented oligomeric channel formation. These studies indicate that it is possible to prevent the generation of neurotoxic oligomers by targeting the cholesterol-binding domain of A beta peptides. This original strategy could be used for the treatment of Alzheimer's and other neurodegenerative diseases that involve cholesterol-dependent toxic oligomers.