Lu Daniel C, Soriano Salvador, Bredesen Dale E, Koo Edward H
Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA.
J Neurochem. 2003 Nov;87(3):733-41. doi: 10.1046/j.1471-4159.2003.02059.x.
The amyloid beta-protein precursor (APP) is proteolytically cleaved to generate the amyloid beta-protein (Abeta), the principal constituent of senile plaques found in Alzheimer's disease (AD). In addition, Abeta in its oligomeric and fibrillar forms have been hypothesized to induce neuronal toxicity. We and others have previously shown that APP can be cleaved by caspases at the C-terminus to generate a potentially cytotoxic peptide termed C31. Furthermore, this cleavage event and caspase activation were increased in the brains of AD, but not control, cases. In this study, we show that in cultured cells, Abeta induces caspase cleavage of APP in the C-terminus and that the subsequent generation of C31 contributes to the apoptotic cell death associated with Abeta. Interestingly, both Abeta toxicity and C31 pathway are dependent on the presence of APP. Both APP-dependent Abeta toxicity and C31-induced apoptotic cell death involve apical or initiator caspases-8 and -9. Our results suggest that Abeta-mediated toxicity initiates a cascade of events that includes caspase activation and APP cleavage. These findings link C31 generation and its potential cell death activity to Abeta cytotoxicity, the leading mechanism proposed for neuronal death in AD.
淀粉样β蛋白前体（APP）经蛋白水解切割后产生淀粉样β蛋白（Aβ），它是阿尔茨海默病（AD）中发现的老年斑的主要成分。此外，有人推测寡聚体和纤维状形式的Aβ可诱导神经元毒性。我们和其他人之前已经表明，APP可被半胱天冬酶在C端切割，产生一种潜在的细胞毒性肽，称为C31。此外，在AD患者而非对照患者的大脑中，这种切割事件和半胱天冬酶激活有所增加。在本研究中，我们表明在培养细胞中，Aβ诱导APP在C端的半胱天冬酶切割，随后产生的C31导致与Aβ相关的凋亡性细胞死亡。有趣的是，Aβ毒性和C31途径均依赖于APP的存在。APP依赖的Aβ毒性和C31诱导的凋亡性细胞死亡均涉及顶端或起始半胱天冬酶-8和-9。我们的结果表明，Aβ介导的毒性引发了一系列事件，包括半胱天冬酶激活和APP切割。这些发现将C31的产生及其潜在的细胞死亡活性与Aβ细胞毒性联系起来，Aβ细胞毒性是AD中神经元死亡的主要提出机制。
