The caspase-derived C-terminal fragment of beta APP induces caspase-independent toxicity and triggers selective increase of A beta 42 in mammalian cells
C. Dumanchin-njock et al., The caspase-derived C-terminal fragment of beta APP induces caspase-independent toxicity and triggers selective increase of A beta 42 in mammalian cells, J NEUROCHEM, 78(5), 2001, pp. 1153-1161
During its physiopathological maturation, the p-amyloid precursor protein u
ndergoes several distinct proteolytic events by activities called secretase
s. In Alzheimer's disease, the main histological hallmark called senile pla
que is clearly linked to the overproduction of the amyloid peptides A beta
40 and A beta 42, two highly aggregable beta APP-derived fragments generate
d by combined cleavages by beta- and gamma -secretases. Recently, an altern
ative hydrolytic pathway was described, involving another category of prote
olytic activities called caspases, responsible for the production of a 31 a
mino acids beta APP C-terminal fragment called C31. C31 was reported to low
er the viability of N2a cells but the exact mechanisms mediating C31-toxici
ty remained to be established. Here we show that the transient transfection
of pSV2 vector encoding C31 lowers by about 80% TSM1 neuronal cells viabil
ity. Arguing against a C31-stimulated apoptotic response, we demonstrate by
combined enzymatic and immunological approaches that C31 expression did no
t modulate basal or staurosporine-induced caspase 3-like activity and pro-c
aspase-3 activation. Furthermore, C31 did not modify Bax and p53 expression
s, poly-(ADP-ribose)-polymerase cleavage and cytochrome c translocation int
o the cytosol. However, we established that C31 overexpression triggers sel
ective increase of A beta 42 but not A beta 40 production by HEK293 cells e
xpressing wild-type beta APP751. Altogether, our data demonstrate that C31
induces a caspase-independent toxicity in TSM1 neurons and potentiates the
pathogenic beta APP maturation pathway by increasing selectively A beta 42
species in wild type-beta APP-expressing human cells.