THE C99 FRAGMENT OF APP REGULATES CHOLESTEROL TRAFFICKING

The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP) in Alzheimer's Disease (AD) is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cholesterol resides, and the endoplasmic reticulum (ER), where most cholesterol regulatory enzymes localize. The transport of cholesterol from the PM to the ER is believed to be activated by a lipid-sensing peptide(s) in the ER that can cluster PM-derived cholesterol into transient detergent-resistant membrane domains (DRMs), also called ER-regulatory pools of cholesterol. When formed, these ER-DRMs induce cholesterol esterification to maintain homeostasis, while attenuating cholesterol synthesis. Here, we show that the 99-aa C-terminal fragment of APP (C99), when delivered to the ER, acts as a lipid-sensing peptide that forms ER-DRMs called mitochondria-associated ER membranes (MAM). In cellular AD models, increased levels of C99 in the ER upregulate the formation of MAMs by inducing the internalization of cholesterol and its trafficking from the PM to the ER. These results suggest a role for C99 as a mediator of cholesterol disturbances in AD.