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

The Amyloid Precursor Protein (APP) undergoes extensive proteolytic processing to produce several biologically active metabolites which affect Alzheimer’s disease (AD) pathogenesis. Sequential cleavage of APP by β- and γ-secretases results in Aβ, while cleavage by α- and γ-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 β- and α-secretase cleavage of APP (sAPPβ/βCTF and sAPPα/αCTF, respectively) and the downstream metabolites Aβ and p3 are seen. These data indicate that APP cleavage by β/α-secretase are increased and suggest that phospholipid asymmetry plays an important role in APP metabolism and Aβ production.