. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest. 2004 Jul;114(1):121-30. PubMed.

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  1. 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.

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    . Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest. 2004 Jul;114(1):121-30. PubMed.

    . 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. PubMed.