The Spires-Jones paper is a very interesting contribution that is pushing live imaging in more and more fascinating directions. The results in these transgenic mice certainly have a corollary in human studies where, for example, most neocortical neurofibrillary tangles in Alzheimer disease are contained within living neurons (Vickers et al., 2003) and that tangle-bearing neurons demonstrate no specific evidence of apoptotic degeneration (Woodhouse et al., 2006). This is not to say that the abnormalities in tau do not cause neurodegeneration, but that the detectable pathological hallmark may be associated with neuronal dysfunction which can be tolerated for long periods of time and may not necessarily result in cell death.

References:
Vickers JC, Tan A, Dickson TC. Direct determination of the proportion of intra- and extra-cellular neocortical neurofibrillary tangles in Alzheimer's disease. Brain Res. 2003 May 2;971(1):135-7. Abstract

Woodhouse A, Dickson TC, West AK, McLean CA, Vickers JC. No difference in expression of apoptosis-related proteins and apoptotic morphology in control, pathologically aged and Alzheimer's disease cases. Neurobiol Dis. 2006 May 1;22(2):323-33. Abstract

View all comments by James Vickers

The link among activated caspases, tangles, and death of neurons has been proposed based on snapshot types of analyses of patient brain, mouse brain, and cells. Experimental evidence for a causal relation was lacking, as most data did not surpass the “chicken-egg” level. It is unclear what is cause, consequence, or correlation.

The Spires-Jones et al. study takes care of that, although only on a short time scale. The most recent study by the group of Michel Goedert goes in the same direction, and does so on a longer time scale (Delobel et al., 2008). Both groups conclude that caspases are unlikely to contribute to tauopathy.

We have assessed in the past, and occasionally still do, in our different transgenic AD models how activated caspases relate to amyloid and tau pathology. We were unable to find a close correlation, also not in the p25 mice in which neurons degenerate “in droves” (Muyllaert et al., 2008). Activated caspase is also not part of the picture in our most recent...  Read more

The link among activated caspases, tangles, and death of neurons has been proposed based on snapshot types of analyses of patient brain, mouse brain, and cells. Experimental evidence for a causal relation was lacking, as most data did not surpass the “chicken-egg” level. It is unclear what is cause, consequence, or correlation.

The Spires-Jones et al. study takes care of that, although only on a short time scale. The most recent study by the group of Michel Goedert goes in the same direction, and does so on a longer time scale (Delobel et al., 2008). Both groups conclude that caspases are unlikely to contribute to tauopathy.

We have assessed in the past, and occasionally still do, in our different transgenic AD models how activated caspases relate to amyloid and tau pathology. We were unable to find a close correlation, also not in the p25 mice in which neurons degenerate “in droves” (Muyllaert et al., 2008). Activated caspase is also not part of the picture in our most recent “combined” Alzheimer model, i.e., bigenic APPxTau mice with amyloid and tau pathology. Moreover, in that same study, we compare with TauxGSK3 bigenic mice (biGT mice) that develop tangles in almost every forebrain neuron with aging, but without killing the neurons (Terwel D, Muyllaert D, Dewachter I, Borghgraef P., Croes S., Devijver H., Van Leuven F., Amyloid activates GSK-3 to aggravate neuronal tauopathy in bigenic mice Am J Pathol. 2008, March issue).

The central issue in AD of “Do tangles kill neurons?,” raised again by Spires-Jones et al., can now be answered with a firm no. On the contrary, the hypothesis that “tangles are protective” gains in weight and might be true, after all! Our upcoming paper on the bigenic mice reinforces this view further.

In summary: tangle formation in itself does not activate caspases. Contributions of activated caspases to neuronal cell death does not involve truncation of tau. Tau truncation in itself is not involved in promoting tangle formation, and tangle formation in itself is not causing cell death. Clearly, other factors, yet to be identified, must exist in the complex chain of events leading to neuronal death.

Negative results are important to exclude “candidates” and stop hypotheses. The new data, even if “they come only out of mouse models,” should inspire us to rethink the AD problem, and invite new hypotheses and new candidates to come forward.

View all comments by Fred Van Leuven

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

View all comments by Troy Rohn