Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases

Alzheimer's disease is characterized by neurodegeneration and deposition of beta A4, a peptide that is proteolytically released from the amyloid precu rsor protein (APP), Missense mutations in the genes coding for APP and for the polytopic membrane proteins presenilin (PS) 1 and PS2 have been linked to familial forms of early-onset Alzheimer's disease. Overexpression of pre senilins, especially that of PS2, induces increased susceptibility for apop tosis that is even more pronounced in cells expressing presenilin mutants. Additionally, presenilins themselves are, targets for activated caspases in apoptotic cells, When we analyzed APP in COS-7 cells overexpressing PS2, w e observed proteolytic processing close to the APP carboxyl terminus. Prote olytic conversion was increased in the presence of PS2-I, which encodes one of the known PS2 pathogenic mutations. The same proteolytic processing occ urred in cells treated with chemical inducers of apoptosis, suggesting a pa rticipation of activated caspases in the carboxyl-terminal truncation of AP P, This was confirmed by showing that specific caspase inhibitors blocked t he apoptotic conversion of APP, Sequence analysis of the APP cytosolic doma in revealed a consensus motif for group LII caspases ((IVL)ExD), Mutation o f the corresponding Asp(664) residue abolished cleavage, thereby identifyin g APP as a target molecule for caspase-like proteases in the pathways of pr ogrammed cellular death.