Localized gene transfer has produced the first rat model of neurofibrillary tangles, announce the authors of a report in the January 2004 American Journal of Pathology. The researchers, led by Ron Klein of Louisiana State University Health Sciences Center in Shreveport, also produced tau pathology in the hippocampus of PS-1/APP double-transgenic mice with their viral vector.

Transgenic mice with neurofibrillary tangles (NFTs) can now be created using the P301L tau mutation that causes the tauopathy frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, tau pathology in these mice takes time—and lots of money—to develop, and the authors write that it is possible that the nervous system adapts to the transgene during development, reducing the relevance of this pathology to Alzheimer's disease. Enter the virus. In addition to addressing these two issues, viral introduction of transgenes offers other advantages, such as within-animal comparisons of unilateral injections, or the ability to work with larger animals such as rats.

Following the groundbreaking work of Rusty Gage and colleagues in modeling polyglutamine repeat disorders via a viral vector (Senut et al., 2000), the approach has been applied to other disease-associated genes, including alpha synuclein (see ARF related news story). In the current report, Klein and colleagues describe their success with a vector construct that combines the P301L tau mutation with the hybrid cytomegalovirus/chicken β-actin (CBA) promoter and the 3' enhancer woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). When transfected into the medial septal region of the basal forebrain of three-month-old male Sprague-Dawley rats, this construct produced tau expression confined to this area within three weeks. By four months, the researchers identified NFTs with immunoelectron microscopy. Constructs that did not include the WPRE were less successful in producing tau expression.

The researchers also report some success with injecting the vectors into the hippocampi of two-month-old PS-1/APP mice, attempting to add tau pathology to a line that produces β-amyloid pathology. Immunolabeling for mutant tau revealed the presence of "tau pretangles" adjacent to amyloid deposits in the transfected hippocampi of these mice at the age of 14 months.

The ability to work in rats, the authors write, will make it easier for researchers to employ various pharmacological and behavioral techniques to probe the effects of tau mutations on the development of NFTs and on Alzheimer's pathology. "For example, the influence of the aged brain can be evaluated by comparing results from vector injections at the same dose and time interval, in either young or old rats," the authors note.—Hakon Heimer

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  1. This article is mostly technical, and only preliminary data are shown. I realize this may sound severe, but I believe we should all keep this caveat in mind, especially given how we are urged to publish.

    Having said that, this work is full of promise. It is now possible to induce neurofibrillary degeneration (NFD) in specific brain areas and at a given time. Since the regional pathway of NFD is well-known in AD, it is now possible to validate the sequential and hierarchical progression of tau pathology in an animal model. Such a model will allow us to understand tau pathology better by asking questions such as: Is this progression true in all animals? Is amyloid necessary to see this progression? Is an aged neuron more vulnerable than a young one? And, of course, which therapeutic intervention is the most useful?
    Does this signal the end of transgenic animals as we know them, or the beginning of a combination of both approaches?

  2. Towards a Relevant Model of Alzheimer’s Disease

    Transgenic mice with mutated APP gene (APP) or APP+PS1 are models of the amyloidosis occurring in familial AD. Transgenic mice with tau are models of familial frontotemporal diseases. Transgenic mice with both APP, PS1 and tau are mice with two different pathologies that still do not reproduce the “natural and molecular history of AD.” Therefore, they are not relevant to the study of sporadic AD that represents 99.5 percent of all AD cases. In the human disease, a synergy between APP and tau pathologies is observed.

    In the paper of Klein et al., tau is transferred in specific brain areas via stereotaxic injections of a viral vector-based system carrying the P301L-mutated tau gene. This approach brings us closer to a relevant model of AD. Indeed, it is well-known that the tauopathy in AD is spreading along a precise pathway of cortico-cortical connections, from the transentorhinal cortex to the neocortex, in perfect alignment with cognitive impairments. Transgenic models of a tauopathy circumscribed to a specific brain area are already at our disposal, using specific promoters. But these models are apparently less convenient than the one proposed in the Klein et al. paper.

    To conclude, this new approach sounds very interesting, and opens the gate of a relevant model of AD. But there is still some work to do. In fact, the real model is the one where, following the “injection” of a tauopathy in the hippocampal area, you will observe a spreading of this tauopathy towards the neocortex, as in sporadic AD. In case of success, this model with a tauopathy expanding under the weight of APP burden will be a relevant target to screen anti-Alzheimer's drugs.

  3. You mentioned that transgenic mice with neurofibrillary tangles can now be created by the use of the P301L tau mutation. Neurofibrillary tangles and amyloid plaques both exist in Alzheimer's patients. Is there concrete evidence that supports the idea that neurofibrillary tangles exist before amyloid plaques or vice versa?

References

News Citations

  1. Viral Transgenic Techniques Pay Off In Parkinson's Models

Paper Citations

  1. . Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain. J Neurosci. 2000 Jan 1;20(1):219-29. PubMed.

Further Reading

Primary Papers

  1. . Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol. 2004 Jan;164(1):347-53. PubMed.