Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, Laferla FM, Rohn TT, Cotman CW.
Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.
J Clin Invest. 2004 Jul;114(1):121-30.
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Caspase Activation But Not Apoptosis
The article by Rissman and colleagues (2004) and accompanying commentary by Dickson (2004) highlight the potential importance of caspase activation in Alzheimer disease (AD). In the former, Rissmann et al. (2004) convincingly show that caspase-cleavage of tau, which may precede the phosphorylation of tau, serves to catalyze filament formation and thereby may be a key step in the development of the hallmark neurofibrillary pathology. However, there are several important caveats to consider here. While caspase activation may play a role in disease, this does not imply that apoptosis is also a feature of disease. Indeed, while there is demonstrable activation of initiator caspases in vulnerable neurons, this apparently does not lead to the cytoplasmic activation of executioner caspases, including the caspase 3 shown by Rissman to effect tau alterations (Raina et al., 2001). In fact, activation of caspase 3, where reported (Stadelmann et al., 1999), is restricted to granules of granulovacuolar degeneration.
Whether the phenomena described by Rissman occur in such granules is unclear. That activation of executioner caspases and bona fide apoptotic mechanisms do not occur in AD (Perry et al., 1998; Raina et al., 2001) is consistent with the protracted course of cell death in AD (Perry et al., 1998). In relation to the work by Rissman, while it is clear that neurofibrillary tangles (NFT) provide a useful correlate of cognitive impairment (Bennett et al., 2004), the decade-plus survival time of NFT-bearing neurons (Morsch et al., 1999) indicates that it is the processes that lead to NFT formation, rather than NFT formation per se, that are most important. In this regard, factors that lead to caspase activation and other early processes such as oxidative stress (Nunomura et al., 2001) are important to understand.
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004 Mar;61(3):378-84. Abstract
Dickson DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J Clin Invest. 2004 Jul;114(1):23-7. Abstract
Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol. 1999 Feb;58(2):188-97. Abstract
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. Abstract
Perry G, Nunomura A, Lucassen P, Lassmann H, Smith MA. Apoptosis and Alzheimer's disease. Science. 1998 Nov 13;282(5392):1268-9. Abstract
Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol (Berl). 2001 Apr;101(4):305-10. Abstract
Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest. 2004 Jul;114(1):121-30. Abstract
Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Bruck W, Jellinger K, Lassmann H. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death. Am J Pathol. 1999 Nov;155(5):1459-66. Abstract