The caspase-derived C-terminal fragment of βAPP induces caspase-independent toxicity and triggers selective increase of Aβ42 in mammalian cells
Journal of Neurochemistry(2001)
摘要
During its physiopathological maturation, the β-amyloid precursor protein undergoes several distinct proteolytic events by activities called secretases. In Alzheimer's disease, the main histological hallmark called senile plaque is clearly linked to the overproduction of the amyloid peptides Aβ40 and Aβ42, two highly aggregable βAPP-derived fragments generated by combined cleavages by β- and γ-secretases. Recently, an alternative hydrolytic pathway was described, involving another category of proteolytic activities called caspases, responsible for the production of a 31 amino acids βAPP C-terminal fragment called C31. C31 was reported to lower the viability of N2a cells but the exact mechanisms mediating C31-toxicity remained to be established. Here we show that the transient transfection of pSV2 vector encoding C31 lowers by about 80% TSM1 neuronal cells viability. Arguing against a C31-stimulated apoptotic response, we demonstrate by combined enzymatic and immunological approaches that C31 expression did not modulate basal or staurosporine-induced caspase 3-like activity and pro-caspase-3 activation. Furthermore, C31 did not modify Bax and p53 expressions, poly-(ADP-ribose)-polymerase cleavage and cytochrome c translocation into the cytosol. However, we established that C31 overexpression triggers selective increase of Aβ42 but not Aβ40 production by HEK293 cells expressing wild-type βAPP751. Altogether, our data demonstrate that C31 induces a caspase-independent toxicity in TSM1 neurons and potentiates the pathogenic βAPP maturation pathway by increasing selectively Aβ42 species in wild type-βAPP-expressing human cells.
更多查看译文
关键词
aβ42,βapp,caspase-derived,c-terminal,caspase-independent
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要