The question of how neurofibrillary tangles (NFTs) contribute to the profound loss of neurons in Alzheimer's disease remains unsettled in part because of a dearth of suitable animal models. A handful of transgenic mouse strains exist that express various forms of tau, but they either die at a young age or differ markedly from the tau pathology seen in AD. Indeed, "the reconstruction of tau pathology in cell and animal models remains an important goal," write researchers led by Eckhard Mandelkow in a paper, published last month, on the structural characteristics that allow human tau mutations to promote tau aggregation in vitro (von Bergen et al. 2001 See also comment by Peter Davies below).

A paper published on New Year's Day provides a step in this direction. Led by Akihiko Takashima of the RIKEN Brain Science Institute in Saitama, Japan, first author Kentaro Tanemura and colleagues report their analysis of tau transgenic mice that enable the study of tau-induced neurodegeneration in vivo. The mice express the V337M mutation of human tau that causes the tauopathy FTDP-17 in addition to wildtype mouse tau. Other mice expressing the stronger P301L tau mutation of FTDP-17 die too young to allow analysis over time.

As 11-month-old adults, the V337M mice have aggregations of phosphorylated human tau predominantly in neurons of the CA1, CA2, and CA3 areas of hippocampus. These neurons appeared to be degenerating and dying by atrophy, though apoptosis was never seen. Moreover, transgene-expressing neurons also accumulated RNA and lacked microtubules. The authors speculate that, by binding to tau, accumulating RNA competes with tau's binding to tubulin, thus leading to microtubule depolymerization and neuronal dystrophy. Previous work has shown that RNA enhances the assembly of tau paired helical filaments in vitro (Kampers et al., 1996.)

In this paper, Tanemura et al. mention that the tau aggregations form a β-sheet structure but stop short of calling the aggregations NFTs. Yet in a paper published last month, they claim that the V337M tau occurs in filaments that satisfy all histological criteria used to identify NFTs as seen in human neurodegenerative diseases (Tanemura et al. 2001.)

Takashima's team also reports weakened neural activity in the hippocampi of their transgenic mice, which they attribute to a smaller number of functional neurons, as well as impaired performance in two rodent behavioral tests. In summary, these mice might enable a more detailed observation of how tau pathology develops over time than was possible before (See also related news item)." The authors also suggest the mice may be useful to test experimental drugs intended to interfere with tangle formation.-Gabrielle Strobel.

Reference:
Tanemura K, Murayama M, Akagi T, Hashikawa T, Tominaga T, Ichikawa M, Yamaguchi H, Takashima A. Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci 2002 Jan 1;22(1):133-41. Abstract

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  1. The Takashima mice are remarkable, as they appear to express high levels of
    the mutant tau protein in only a very few cells in the brain: that is, in
    some of the pyramidal cells of the hippocampus. Apparently the transgene is expressed at only very low levels in the rest of the brain, although it is possible that there are other cell groups that also show high expression. In the pyramidal cells, it appears that
    high-level expression of the mutant tau protein leads to hyperphosphorylation, some aggregation (although it is unclear exactly how much aggregation there is), and cell dysfunction. Because of the very limited number of cells expressing the mutant protein, it appears that the mice will survive (unlike the Lewis/Hutton mice) to advanced age. The authors state that up to 70 percent of the tau in the hippocampus is the mutant protein, and this would suggest that the level of mutant human tau in the pyramidal cells is several fold above normal. This may also be why the cells are sick. High levels of a mutant tau protein are probably bad for cells. It is unclear what relevance these mice may have for studies of
    Alzheimer's disease, but it is an interesting model of tau-mediated cell dysfunction in the hippocampus.

    In related news, the Mandelkow's paper continues their fine work trying to
    unravel the mechanism of PHF formation by in vitro studies of structural changes that occur in tau on aggregation. Their identification of regions of tau that seem to be important for aggregation through beta-sheet formation is probably relevant to the mechanism of PHF formation in AD. They are the only group (to my knowledge) to be able to show formation of true paired helical filament structures using mutant tau constructs. Although this is a rather esoteric point, there is some debate about whether neuronal death in the tau mutation cases involves PHF formation as a necessary step. In one of the mutations they use in their study, P301L, the human disease does not appear to involve extensive PHF formation. The
    Mandelkows discuss the possible mechanisms of cell death in tau mutation cases at some length, and it is clear that in most cases, more than one mechanism might participate in killing cells. However, these mechanistic studies point to important hypotheses that can be tested in cellular and perhaps animal models. For example, it will be very interesting to see if
    transgenic mice with the deletion of lysine at position 280 would show early and extensive PHF formation, as this in vitro work clearly suggests. No doubt attempts to make these mice are already underway.

  2. Reply by Akihiko Takashima

    Regarding Peter Davies' comment, I would like to reply. We observed human tau expression in the entire brain where the PDGF promoter activates. In the hippocampus region, exogenously expressing human tau is highly accumulated in neurons, and some neurons exhibited positive staining for histological markers for NFTs. This may be not due to higher expression of human tau specifically in hippocampus of Tg mice, but to the reduction of tau degradation. Human tau mRNA expression was almost the same level as endogenous mouse tau, despite the fact that human tau protein level was only 10 percent of endogenous tau in other brain areas. Now we don't know what mechanism is involved in the degradation of exogenous tau, and why the degradation of tau is inhibited in hippocampal neurons of aged Tg mice. Because NFTs frequently occur in the hippocampus of aging and AD brain, I think that these are important points to resolve the mechanism of neurodegeneration through tau accumulation in AD.

    Regarding the relevance of FTDP-17 Tg mice to the study of AD: as we know,
    Aβ accumulation may be a cause of AD. AβPP Tg mice with FAD mutation showed Aβ deposition and behavioral change but no neuronal loss or NFTs. Recently, the crossbreeds of tau Tg with AβPP Tg mice resulted in accelerated NFT formation, and Aβ injection into hippocampus of tau Tg mice showed the formation of NFTs in amygdala (Lewis et al,
    2001
    ; Gotz et al. 2001; see related news item). It is possible to interpret these results such that Aβ can accelerate NFT formation when tau is accumulated in the cytoplasm of neurons.

    In normal aging, neurons in the entorhinal cortex and hippocampus can form NFTs without forming Aβ deposition by age 75, suggesting that the process of brain aging activates the formation of NFTs via an Aβ-independent mechanism. If FTD-17 mutations of tau are an accelerating factor for the process of brain aging, and brain aging in mutant tau Tg mice is progressing faster compared to normal mice, then Aβ deposition further accelerates the brain aging and formation of NFTs.

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References

News Citations

  1. Finally Introducing: A Mouse with Wildtype Human Tau That Makes Tangles

Paper Citations

  1. . Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci. 2002 Jan 1;22(1):133-41. PubMed.

External Citations

  1. von Bergen et al. 2001
  2. Kampers et al., 1996
  3. Tanemura et al. 2001

Further Reading

Papers

  1. . Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci. 2002 Jan 1;22(1):133-41. PubMed.

News

  1. Finally Introducing: A Mouse with Wildtype Human Tau That Makes Tangles
  2. Finally United? Aβ Found to Influence Tangle Formation

Primary Papers

  1. . Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci. 2002 Jan 1;22(1):133-41. PubMed.