Alonso Ad, Li B, Grundke-Iqbal I, Iqbal K.
Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity.
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9.
Please login to recommend the paper.
To make a comment you must login or register.
While this study helps us to understand some of the actions of tau, several questions come to mind.
Alzheimer disease (AD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Guam parkinsonism dementia, cortical basal degeneration, dementia pugilistica, Pick’s disease, progressive supranuclear palsy, and tangle-only dementia, among other tauopathies, are linked to the progressive accumulation of filamentous hyperphosphorylated tau inclusions. Besides the accumulation of tau, another distinctive feature is the loss of neuritic arborization and the disruption of microtubules and synaptic terminals. This neurodegeneration is also present in FTDP-17, diseases linked to tau mutations, pointing to tau and tau function as the origin of dementia. Shahani et al. recently described a very interesting model to test the role of hyperphosphorylated tau in neurodegeneration; they infected neurons in mouse brain slices with pseudo-hyperphosphorylated tau using recombinant Sindbis virus. This method allows the authors to study behavior of hyperphosphorylated tau in living neurons. The expressed tau filled up the neurons highlighting all the processes. In this paradigm, spines and dendrites were not altered, but neurons underwent apoptosis—an acute cell death. This scenario is markedly different from AD where neurofibrillary degeneration is a slow, chronic, progressive cell death associated with a retrograde degeneration, that is, loss of spines and dendrites.
We have shown that hyperphosphorylated tau from AD brains inhibits and disrupts microtubules probably by sequestering normal tau, MAP1, and MAP2 (Alonso et al., 1994, 1996, 1997, 2001), and that on aggregation into filaments this pathological tau loses its inhibitory activity (Alonso et al., 2006). Shahani et al. pointed out that synaptic loss might require Aβ pathology, a second hallmark of AD, which is lacking in the mouse brain slice model. Though one cannot rule out the possible role of Aβ in AD-type neurofibrillary degeneration, there are several other more likely explanations for the lack of synaptic loss in the mouse slice model which ought to be considered.
For example, the pseudophosphorylated tau is not AD-like abnormally hyperphosphorylated tau. One should at least verify whether, like the AD p-tau, the pseudophosphorylated protein sequesters normal MAPs and inhibits and disrupts microtubule assembly (see Alonso, et al. 1994, 1996, 1997). The AD p-tau has been shown to self-assemble in vitro into bundles of paired helical filaments (Alonso, et al., 2001). The dynamics of the self-assembly of the pseudophosphorylated tau may be compared with those of AD p-tau.
The level of tau expression in neurons in the model was several-fold higher than the endogenous tau expression. It is possible that the presence of such a high level of protein increases the chances of misfolding. This could induce stress in the neurons, triggering apoptosis independent of tau physiological function. The expression of pseudophosphorylated tau, even with the limitation of the mutation to glutamic acid to mimic phosphorylation, means the appearance in the cytosol of a molecule of tau phosphorylated at 10 sites. It is unlikely that tau gets phosphorylated at all the sites simultaneously in vivo. In fact, our in vitro studies suggest that tau phosphorylation is a stepwise process where the ability to sequester normal tau is acquired at ~4-6 moles of phosphate per mole of protein, and tau is able to self-assemble at ~10 moles of phosphate per mole of protein. This suggests a sequential change of conformation (Alonso et al., 2004). In this context, the nature of the sites selected for mutation is very important. One significant absence in this selection in the mouse slice model by Shahani et al. was Ser262, one of the tau phosphorylation sites implicated in tau-tubulin binding and a site that has been found to be phosphorylated in most of the tauopathies.
In short, the approach presented by Shahani et al. appears to be quite attractive to study tau phosphorylation. However, a number of refinements might be required for such a model to reproduce the scenario found in Alzheimer disease brains.
Microscopic observation of many regions of the brain in advanced AD reveals, in addition to ghost tangles, a very high density of presumably still living neurons exhibiting an intact nucleus and also with a dense accumulation of neurofibrillary tangles (NFTs). Logic suggests that if a neuronal state is fleeting, it should be observed only rarely in the slice of time seen in fixed tissue under a microscope. On the other hand, if a neuronal state is long-lasting, one can expect to see it represented in many neurons in a slice of time—as is the case of apparently living neurons containing NFTs in AD brains. It is possible to derive counts in the hippocampus of these living neurons containing NFTs and combine these data with data, for example, of Mark West on numbers of neurons in hippocampus and rate of neuron loss in AD, to derive an estimate of how long a neuron may live, on average, after it has developed frank NFTs. The answer is clear that such neurons live for decades, suggesting that NFTs may not be the cause of their ultimate death (Morsch, Simon, and Coleman). This conclusion is consistent with earlier data of Gomez-Isla et al. (1997) that NFTs cannot fully account for the neuronal loss seen in AD. There are ample other factors that have been implicated in neuron death in AD.