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


  1. In this study, Boekhoorn et al. investigated synaptic plasticity, learning, and memory in young versus aged tauP301L mice. They found that learning in the novel object paradigm was significantly better in young tauP301L mice when compared to a control group. In addition, long-term potentiation, which is commonly viewed as a molecular correlate for learning and memory, was found to be enhanced in tauP301L mutant mice when measured in the perforant path-dentate gyrus pathway of the hippocampus. These findings are very surprising, since the tauP301L mutation is linked to frontotemporal dementia with parkinsonism (FTDP-17) in humans, and tau pathology is one of the hallmarks of the pathogenesis of Alzheimer disease (AD). Consistently inducible overexpression of tauP301L in the forebrain of mice causes severe cognitive deficits in aged mice (Santacruz et al., 2005).

    Although the mechanism by which tauP301L causes facilitated memory in young mice is not clear (Boekhoorn et al. ruled out morphological changes or neurogenesis in the hippocampus as underlying mechanisms), these findings are interesting in view of the previously formulated hypothesis that a failure in neuroplasticity may be the common feature in the pathogenesis of sporadic AD (Mesulam, 1999; Arendt, 2004). This hypothesis predicts that tau and APP are plasticity factors that, when deregulated, cause a failure in neuroplasticity which eventually leads to the manifestation of amyloid plaques and neurofibrillary tangles and neuronal loss. That overexpression of a mutant tau initially facilitates learning and synaptic plasticity but eventually contributes to cognitive impairment, and neuronal cell death fits this hypothesis very well. In line with this observation, our laboratory recently demonstrated that expression of p25, the truncated form of the cyclin-dependent kinase 5 (Cdk5) activator p35, initially facilitates synaptic plasticity, learning, and memory in mice (Fischer et al., 2005). Cdk5/p25 has been implicated in the pathogenesis of AD in humans, and consistently we found that chronically elevated p25 levels lead to severe neuronal and synaptic loss accompanied by impaired learning and memory in mice (Fischer et al., 2005). In summary, this data seem to support the idea that the main players implicated in the pathogenesis of sporadic AD might normally function as mediators of neuroplasticity, as long as their activity is tightly controlled. Future research is needed to identify and understand the processes that deregulate tau, Cdk5, and APP signaling and to understand the interaction among these potential plasticity factors. This will not only help to further understand learning and memory but also to identify novel strategies to prevent Alzheimer disease.


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    . Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron. 2005 Dec 8;48(5):825-38. PubMed.

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  2. This study of a beneficial effect of tau as shown by improved long-term
    potentiation, in the absence of tau hyperphosphorylation, demonstrates
    that tau mutations, such as P301L, are not per se causing cognitive
    decline. As this research group has in the past also generated human
    wild-type tau transgenic mice without carrying mutations, it would be
    an interesting follow-up study to repeat the electrophysiology, Golgi
    stainings, and the analysis of neurogenesis with these mice to determine
    whether higher wild-type tau levels would lead to even more improvement.

  3. Boekhoorn and colleagues indicated that their P301L tau transgenic mice showed higher LTP and memory performance when they are young—before NFTs and hyperphosphorylation have occurred yet. But Mandelkow’s group found that tau overexpression inhibits the anterograde transport along microtubules by obstructing kinesin movement; their result was rather opposite.

    If P301L mutant tau binds to the microtubule, axonal transport should be inhibited, leading to synaptic dysfunction. However, young Tg mice exhibited “improvement” of synaptic function compare to non-Tg mice. Tau overexpression may, therefore, have two effects. On the one hand, it improves synaptic function in young mice, and on the other, it causes neurodegeneration through hyperphosphorylation and aggregation in cytoplasm of older animals. In the case of human brain, tau never gets overexpressed during the entire lifespan. Tau does accumulate in the case of FTDP-17, where it induces NFTs and neuronal loss without overexpression. Therefore, we need to clarify the effects of tau mutations, rather than overexpression, on neuronal function for understanding the mechanism of neurodegeneration in human tauopathies, including AD. In this sense, by comparing P301L mutant with wild-type tau Tg mice, we may be able to understand what factors play the critical role in neuronal dysfunction in tauopathies.

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News Citations

  1. Early Events in AD Mice as Targets for Therapy
  2. No Toxicity in Tau’s Tangles?

Paper Citations

  1. . Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. PubMed.

Further Reading

Primary Papers

  1. . 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. PubMed.