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Review
. 2024 Jul;53(1):455-486.
doi: 10.1146/annurev-biophys-062823-023436. Epub 2024 Jun 28.

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

George A Pantelopulos  1 , Conor B Abraham  1 , John E Straub  1
Affiliations
Review

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

George A Pantelopulos et al. Annu Rev Biophys. 2024 Jul.

Abstract

Cholesterol has been conjectured to be a modulator of the amyloid cascade, the mechanism that produces the amyloid-β (Aβ) peptides implicated in the onset of Alzheimer's disease. We propose that cholesterol impacts the genesis of Aβ 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 Aβ 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.

Keywords: amyloid precursor protein; cellular compartment; cholesterol; lipid bilayer; lipid phase; molecular dynamics.

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