Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease

Cholesterol has been conjectured to be a modulator of the amyloid cascade, the mechanism that produces the amyloid-beta (A beta) peptides implicated in the onset of Alzheimer's disease.We propose that cholesterol impacts the genesis of A beta not through direct interaction with proteins in the bilayer, but indirectly by inducing the liquid-ordered phase and accompanying liquid-liquid phase separations, which partition proteins in the amyloid cascade to different lipid domains and ultimately to different endocytotic pathways.We explore the full process of A beta genesis in the context of liquid-ordered phases induced by cholesterol, including protein partitioning into lipid domains, mechanisms of endocytosis experienced by lipid domains and secretases, and pH-controlled activation of amyloid precursor protein secretases in specific endocytotic environments. Outstanding questions on the essential role of cholesterol in the amyloid cascade are identified for future studies.