A. Weidemann et al., Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases, J BIOL CHEM, 274(9), 1999, pp. 5823-5829
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.