9 April 2006. Recent work with mouse models of Alzheimer disease has driven home the idea that toxic soluble oligomers of the amyloid-β peptide sow their seeds of destruction right from their first appearance, and long before the formation of plaques (see ARF related news story). But little notice has been taken of Aβ’s partner in crime, the microtubule binding protein tau, at those early stages. Dogma has it that the progressive accumulation of tau in a hyperphosphorylated form, and eventually as neurofibrillary tangles, creates neurotoxicity in AD, as well as in the inherited frontotemporal dementias (FTD) caused by tau mutations. Then, just as for plaques and AD, data emerged to suggest that the accumulation of neurofibrillary tangles does not correlate closely with neuronal toxicity or behavioral defects in mouse models of FTD (see ARF related news story and Andorfer et al., 2005).
So what’s going on with tau? Something surprising, it turns out. According to a new study from Paul Lucassen at the University of Amsterdam, and Fred van Leuven at the University of Leuven in Belgium and their colleagues in Amsterdam and Osaka, Japan, 2-month-old mice overexpressing a mutant form of human tau protein not only show no ill effects, but have significantly better memory than their non-transgenic counterparts. These same mice are destined to develop tau hyperphosphorylation, neurofibrillary tangles, and neurodegeneration later on, but in the first few months, they show increased long-term potentiation in the dentate gyrus region of the hippocampus, and better performance on an object recognition test.
The work, which appeared in the March 29 Journal of Neuroscience, reveals an unexpected positive effect of mutant tau on hippocampal synapses, and suggests the protein may play a role in normal hippocampal memory processes. The authors conclude tau mutations per se do not render the protein toxic, but that the ensuing hyperphosphorylation is a critical step in tau pathogenesis.
First author Karin Boekhoorn, from the Lucassen lab, collaborated with second author Dick Terwel, at the Van Leuven lab, to study young (8 to 10 weeks old) transgenics carrying the P301L mutation in the human tau gene. By immunohistochemistry and Western blotting with three different anti-phospho-tau antibodies, tau appeared minimally phosphorylated, and modification of the mutant appeared lower than in either wild-type tau4R transgenic or non-transgenic mice, consistent with previous work (Terwel et al., 2005).
But when the researchers measured synaptic function in the hippocampus, they got an unexpected result. Mutant tau expression had no effect on field potentials, but did cause an increase in induced LTP in the dentate gyrus, compared to wild-type protein. The transgene had no effect on LTP in the CA1 region.
Enhanced LTP was associated with increased memory performance by the tau mutant mice in an object recognition test. The experiment involved placing two objects in with the mice, and recording the time spent exploring each item. When an item was presented twice, exploration time should decrease if the mice remembered seeing it before. When recall was tested after one hour, the nontransgenic mice performed as well as mutant tau mice, but after 3.5 hours, the mutant tau transgenics were significantly better at discriminating between the novel and familiar objects. This test was used, rather than a water maze, because the young mice already showed motor deficits as a result of tau expression. But the results were not affected by their movement problems, since even 5-week-old mice showing no motor deficits were significantly better at object recognition.
The researchers found no change in hippocampal morphology, including volume, dendrite number or length, that could account for the effect of mutant tau. Since tau expression affects the cell cycle, neuronal maturation, and axonal elongation, they also looked at hippocampal neurogenesis, but saw no effect of the transgene on birth, proliferation, or survival of new neurons.
The authors concede that there is no way to know if the effects they see on memory are due to the tau mutation or might also be seen with overexpression of wild-type tau itself. Young transgenic mice expressing the tau4R isoform have their own problems and cannot be directly compared to the mutants in these tests. Nonetheless, this study supports the hypothesis that progressive tau hyperphosphorylation with age is the critical factor in tau toxicity. With other studies suggesting that NFTs are not toxic themselves, attention is now pointing toward some form of soluble, pre-tangle, hyperphosphorylated tau in neurotoxicity, perhaps analogous to the soluble Aβ species currently under intense study.—Pat McCaffrey.
Boekhoorn K, Terwel D, Biemans B, Borghgraef P, Wiegert O, Ramakers GJ, de Vos K, Krugers H, Tomiyama T, Mori H, Joels M, van Leuven F, Lucassen PJ. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. Abstract