Raina A K, Hochman A, Zhu X, Rottkamp C A, Nunomura A, Siedlak S L, Boux H, Castellani R J, Perry G, Smith M A
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Acta Neuropathol. 2001 Apr;101(4):305-10. doi: 10.1007/s004010100378.
Multiple studies suggest that neuronal death in Alzheimer's disease (AD) is the result of an apoptotic mechanism. However, the stereotypical manifestations that define the terminal phases of apoptosis, such as chromatin condensation, apoptotic bodies, and blebbing, are not seen in AD. In this study, we show that the caspases, such as caspase 6, which cleave amyloid-beta protein precursor (A beta PP) and presenilins, are localized to the pathological lesions associated with AD. However, while upstream caspases such as 8 and 9 are clearly found in association with the intraneuronal pathology in AD, downstream caspases such as 3, 6 and 7 are present only at control levels. Given that execution of apoptosis requires amplification of the caspase-mediated apoptotic signal, our results indicate that in AD there is a lack of effective apoptotic signal propagation to downstream caspase effectors. Therefore, while the presence of caspases, especially caspase 6, in association with extracellular deposits of amyloid-beta, could obviously have important ramifications on the proteolytic processing of A beta PP and, thereby, on disease pathogenesis, it seems that AD represents the first in vivo situation reported in which the initiation of apoptosis does not proceed to caspase-dependent cell death. This novel phenomenon of apoptotic avoidance, which we term abortive apoptosis, or abortosis, may represent an exit from the caspase-induced apoptotic program that leads to neuronal survival in AD.
多项研究表明，阿尔茨海默病（AD）中的神经元死亡是凋亡机制的结果。然而，在AD中并未观察到定义凋亡末期的典型表现，如染色质浓缩、凋亡小体和细胞膜起泡。在本研究中，我们发现，诸如切割淀粉样β蛋白前体（AβPP）和早老素的半胱天冬酶6等半胱天冬酶定位于与AD相关的病理病变处。然而，虽然在AD的神经元内病理中明显发现了上游半胱天冬酶8和9，但下游半胱天冬酶3、6和7仅处于对照水平。鉴于凋亡的执行需要半胱天冬酶介导的凋亡信号放大，我们的结果表明，在AD中缺乏有效的凋亡信号向下游半胱天冬酶效应器的传播。因此，虽然半胱天冬酶，尤其是半胱天冬酶6，与细胞外淀粉样β沉积物有关，这显然可能对AβPP的蛋白水解加工以及疾病发病机制产生重要影响，但AD似乎代表了首次报道的体内情况，即凋亡的启动并未导致依赖半胱天冬酶的细胞死亡。这种我们称为流产性凋亡或夭折的新型凋亡逃避现象，可能代表了从半胱天冬酶诱导的凋亡程序中退出，从而导致AD中的神经元存活。
