Abortive apoptosis in Alzheimer's disease

Multiple studies suggest that neuronal death in Alzheimer's disease (AD) is the result of an apoptotic mechanism. However, the stereotypical manifesta tions that define the terminal phases of apoptosis, such as chromatin conde nsation, 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 pr otein precursor (A beta PP) and presenilins, are localized to the pathologi cal 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 leve ls. 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 effecters. Therefore, while the presence of caspases, especially caspase 6, in associ ation with extracellular deposits of amyloid-beta, could obviously have imp ortant ramifications on the proteolytic processing of A beta PP and, thereb y, on disease pathogenesis, it seems that AD represents the first in vivo s ituation 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 A D.