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Spires-Jones TL, de Calignon A, Matsui T, Zehr C, Pitstick R, Wu HY, Osetek JD, Jones PB, Bacskai BJ, Feany MB, Carlson GA, Ashe KH, Lewis J, Hyman BT. In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J Neurosci. 2008 Jan 23;28(4):862-7. PubMed.
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University of Tasmania
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. PubMed.
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;22(2):323-33. PubMed.
KULeuven
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.
References:
Delobel P, Lavenir I, Fraser G, Ingram E, Holzer M, Ghetti B, Spillantini MG, Crowther RA, Goedert M. Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy. Am J Pathol. 2008 Jan;172(1):123-31. PubMed.
Muyllaert D, Terwel D, Kremer A, Sennvik K, Borghgraef P, Devijver H, Dewachter I, Van Leuven F. Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. Am J Pathol. 2008 Feb;172(2):470-85. Epub 2008 Jan 17 PubMed.
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