Biological Models in Frontotemporal Dementias

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Publisher Summary

This chapter describes that neurofibrillary tangles (NFT) are, with senile plaques, the hallmark neuropathological lesions used for the neuropathological diagnosis of Alzheimer's disease. The intensity of these lesions, particularly NFT, is correlated with the severity of the dementing syndrome. NFT are constituted of bundles of abnormal filaments, called paired helical filaments (PHF), accumulating in neurons in this disease. NFT are also a key lesion of other neurodegenerative diseases, such as frontotemporal dementias (FTD), corticobasal degeneration, Pick's disease, and progressive supranuclear palsy. Many different models of cellular lesions found in tauopathies are now available. Most convincing models highlight the role of tau hyperphosphorylation in neurodegeneration as an essential aspect of NFT formation. In models developing NFT, the brain distribution of these lesions is variable, and might not reflect the exact topography of brain lesions in human diseases. The reproduction of NFT formation in animal models will help in the analysis of neuronal dysfunction linked to these neuronal lesions common to several neurodegenerative diseases.

Section snippets

The neurofibrillary lesions of Alzheimer's disease and related tauopathies

Neurofibrillary tangles (NFT) are, with senile plaques, the hallmark neuropathological lesions used for the neuropathological diagnosis of Alzheimer's disease (Brion, 2005). The intensity of these lesions, particularly NFT, is correlated with the severity of the dementing syndrome. NFT are constituted of bundles of abnormal filaments, called paired helical filaments (PHF), accumulating in neurons in this disease. NFT are also a key lesion of other neurodegenerative diseases, such as

General features

Many transgenic lines expressing wild‐type tau proteins or mutant tau proteins have been generated to try to reproduce in animal models the neurofibrillary pathology. Other transgenic models expressing other factors susceptible to modulate the formation of these lesions (e.g., protein kinases, phosphatases) have also been investigated. Although often focused on the analysis of NFT formation and their pathological effects, these studies have also documented pathological effects independent of

Conclusion

Many different models of cellular lesions found in tauopathies are now available. Most convincing models highlight the role of tau hyperphosphorylation in neurodegeneration as an essential aspect of NFT formation. Careful attention should, however, be paid to the exact characteristics of each model, and to the respective contribution of a loss of function or a gain of “toxic” function. Overexpression of tau alone can induce a pathology linked to disturbances of axoplasmic transports.

Acknowledgements

The author is supported by grants from the Belgian Pôle d' attraction Interuniversitaire (P6/43), the Fonds pour la Recherche Scientifique Mèdicale, and the Fondation pour la Recherche sur la Maladie d' Alzhermier.

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