Regulation of the amyloid precursor protein adaptor proteins by cholesterol and isoprenoids

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and its prevalence is expected to triple in the next fifty years. Each year thousands of people develop the characteristic signs of AD which include progressive dementia, cognitive decline, and personality changes. Aggregation and deposition of amyloid-beta (Abeta) along with intraneuronal accumulation of hyperphosphorylated protein tau are the key histological markers of AD, which lead to neuroinflammation, and ultimately to neuronal cell death. An understanding of the regulation of the amyloid precursor protein (APP), from which Abeta peptide is derived, is required for the development of therapeutics targeted to reduce Abeta deposition while maintaining normal brain physiological function. Our data indicate that two APP adaptor proteins, Fe65 and Mint1/X11alpha are regulated by cholesterol and isoprenoids. Using human autopsy brain, an animal model of aging, and cultured cells, we examined the role of cholesterol and isoprenoids in the regulation of the APP adaptor proteins and the subsequent processing of APP. Cholesterol is involved in diverse physiological processes including cell membrane rigidity, cell signaling, and enzyme activity. The isoprenoids, a product of the cholesterol synthetic pathway, are required for the localization of proteins and for the functionality of many small G-proteins. Together, these molecules play a role in the regulation of APP adaptor proteins.