Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform

Takeshi Ishihara, Ming Hong, Bin Zhang, Yasushi Nakagawa, Michael K. Lee, John Q. Trojanowski, Virginia M.Y. Lee

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506 Scopus citations


Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similar to FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).

Original languageEnglish (US)
Pages (from-to)751-762
Number of pages12
Issue number3
StatePublished - Nov 1999

Bibliographical note

Funding Information:
We thank Dr. A. Hirano for providing tissue block of ALS/PDC; the Biomedical Imaging Core Facility of the University of Pennsylvania for assistance in the EM studies; Dr. M. L. Schmidt for PSP and FTDP-17 sections; and N. Shah, E. Heatherby, K. H. Szymczyk, and Grace Kim for technical assistance. This work was supported by grants from the National Institute on Aging.


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