Abortive apoptosis in Alzheimer's disease

Abstract

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-β protein precursor (AβPP) 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-β, could obviously have important ramifications on the proteolytic processing of AβPP 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 cas-pase-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.

Mechanisms of Cell Death in Neurodegenerative Diseases: Fashion, Fiction, and Facts

“…As a result, novel descriptive terms have been devised to more accurately describe the various cell death types which occur in neurodegenerative disorders. Examples include aposklesis (6), paraptosis (32), abortosis (26), and, the more traditional, autophagia (29) ( Table 1). Difficulties in defining forms of neuronal cell death have also arisen from the fact that the vast majority of studies have been undertaken in the fields of cancer and immunology (3), with many investigators assuming that these cell death features are the same for neurones (19).…”

Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer’s disease

“…In AD, cell loss is another major characteristic and enzymes involved in apoptosis, such as cysteine aspartate proteases, including activated caspases (caspases 3, 6, 8 and 9), are increased in hippocampal and temporal cortical neurons in AD brains (Raina et al 2001;Rohn et al 2001Rohn et al , 2002Matsui et al 2006). While it is likely that these proteases contribute to neurodegeneration, whether this relates to bona fide apoptosis remains obscure (Raina et al 2001(Raina et al , 2003Rohn et al 2001Rohn et al , 2002Zhu et al 2004Zhu et al , 2006. On the other hand, the role of caspase-3 in the cleavage of tau at D 421 is irrefutable (Gamblin et al 2003b;Rissman et al 2004).…”

Neuroprotective properties of Bcl‐w in Alzheimer disease

“…The causes and mechanisms underlying such neuronal death are extremely controversial and none more so than whether apoptosis plays a role. On the one hand, neurons in AD face a wide assortment of apoptotic stimuli including oxidative stress (Zhu et al 2003), amyloid-b (Yankner 1996) and metabolic compromise (Vander Heiden et al 2000), which likely contribute to the expression or activation of apoptotic markers such as Par-4 and caspase family members (Guo et al 1998;LeBlanc et al 1999;Selznick et al 1999;Raina et al 2001). On the other hand, the absence of the hallmark end stage signs of apoptosis, such as nuclear chromatin condensation, apoptotic bodies and other histopathological and morphological manifestations of apoptosis in AD, cast doubt on whether such apoptotic stimuli actually lead to cell death in AD (Perry et al 1998a(Perry et al ,b, 2001Stadelmann et al 1998).…”

“…On the other hand, the absence of the hallmark end stage signs of apoptosis, such as nuclear chromatin condensation, apoptotic bodies and other histopathological and morphological manifestations of apoptosis in AD, cast doubt on whether such apoptotic stimuli actually lead to cell death in AD (Perry et al 1998a(Perry et al ,b, 2001Stadelmann et al 1998). Indeed, the temporal dichotomy between the acute nature of apoptosis versus the chronic duration of AD suggests that, despite initiation, the apoptotic process in AD does not proceed to the point of cell death by classic mechanisms (Perry et al 1998a;Raina et al 2001). To this end, we speculated that survival factors that prevent propagation of the apoptotic signaling pathways would lead to termination, or at least delay, of the classic apoptotic cascade in neurons in AD.…”