This is a provocative study. It clearly supports the idea that caspase activation lies upstream of tangle evolution. Much of the data in this study validates what our group has been investigating in the postmortem AD brain for the past 10 years.

As far back as 2001 (Rohn et al., 2001), we put forth a hypothesis that caspase activation and cleavage of tau are early events that may precede tangle formation. We confirmed this idea in a 2002 study (Rohn et al., 2002), whereby we were the first to demonstrate the caspase-cleavage of tau in the human AD brain. In this paper, we actually provided data involving caspase-9 in the human AD brain that are now explained by Brad Hyman's group. In our 2002 study, a quantitative analysis indicated that as the number of neurons containing neurofibrillary tangles (NFTs) increased, the extent of caspase-9 activation decreased, supporting the idea that caspase-9 activation may precede NFT formation. As Hyman and colleagues show, caspase activation is initiated, but then for some reason is no longer evident, in the same tangle-bearing neuron,...  Read more

This is a provocative study. It clearly supports the idea that caspase activation lies upstream of tangle evolution. Much of the data in this study validates what our group has been investigating in the postmortem AD brain for the past 10 years.

As far back as 2001 (Rohn et al., 2001), we put forth a hypothesis that caspase activation and cleavage of tau are early events that may precede tangle formation. We confirmed this idea in a 2002 study (Rohn et al., 2002), whereby we were the first to demonstrate the caspase-cleavage of tau in the human AD brain. In this paper, we actually provided data involving caspase-9 in the human AD brain that are now explained by Brad Hyman's group. In our 2002 study, a quantitative analysis indicated that as the number of neurons containing neurofibrillary tangles (NFTs) increased, the extent of caspase-9 activation decreased, supporting the idea that caspase-9 activation may precede NFT formation. As Hyman and colleagues show, caspase activation is initiated, but then for some reason is no longer evident, in the same tangle-bearing neuron, similar to what we found with activated caspase-9 in the human AD brain.

We believe the time has come to test whether caspase inhibitors are a viable approach for the treatment of AD. Personally, it has been very difficult to obtain funding for such studies even in mouse models of AD due to concerns by reviewers regarding toxicity. But until studies are actually carried out testing whether caspase inhibitors work, one can only speculate on the relative risk versus reward of using caspase inhibitors as therapeutic agents (Rohn, 2010).

References:
Rohn TT, Head E, Su JH, Anderson AJ, Bahr BA, Cotman CW, Cribbs DH. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease. Am J Pathol. 2001 Jan;158(1):189-98. Abstract

Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain. Neurobiol Dis. 2002 Nov;11(2):341-54. Abstract

Rohn TT. The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities. Apoptosis. 2010 Feb 3. Abstract

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