Loss of CDC50A function drives Aβ/p3 production via increased β/α-secretase processing of APP

Abstract

The Amyloid Precursor Protein (APP) undergoes extensive proteolytic processing to produce several biologically active metabolites which affect Alzheimers disease (AD) pathogenesis. Sequential cleavage of APP by {beta}- and {gamma}-secretases results in A{beta}, while cleavage by - and {gamma}-secretases produces the smaller p3 peptide. Here we report that in cells in which the P4-ATPase flippase subunit CDC50A has been knocked out, large increases in the products of {beta}- and -secretase cleavage of APP (sAPP{beta}/{beta}CTF and sAPP/CTF, respectively) and the downstream metabolites A{beta} and p3 are seen. These data indicate that APP cleavage by {beta}/-secretase are increased and suggest that phospholipid asymmetry plays an important role in APP metabolism and A{beta} production.