Klein RL, Lin WL, Dickson DW, Lewis J, Hutton M, Duff K, Meyer EM, King MA.
Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau.
Am J Pathol. 2004 Jan;164(1):347-53.
PubMed.
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?
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.
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?
Comments
Lille Neuroscience & Cognition
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?
View all comments by Luc BueeDoes this signal the end of transgenic animals as we know them, or the beginning of a combination of both approaches?
Inserm
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.
View all comments by Andre DelacourteEast Tennessee State University, UAB, University of Alabama
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?
View all comments by Maria GonzalesMake a Comment
To make a comment you must login or register.