Abortive apoptosis in Alzheimer's disease

A. K. Raina, A. Hochman, X. Zhu, Catherine Rottkamp, A. Nunomura, S. L. Siedlak, H. Boux, R. J. Castellani, G. Perry, M. A. Smith

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)305-310
Number of pages6
JournalActa Neuropathologica
Volume101
Issue number4
StatePublished - Jan 1 2001
Externally publishedYes

Keywords

  • Alzheimer disease
  • Apoptosis
  • Caspases
  • Neurofibrillary pathology
  • Neuronal survival

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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