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01-05-2014 | Original Paper

Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice

Authors: Tomohiro Umeda, Satomi Maekawa, Tetsuya Kimura, Akihiko Takashima, Takami Tomiyama, Hiroshi Mori

Published in: Acta Neuropathologica | Issue 5/2014

Abstract

Senile plaques comprised of Aβ aggregates and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments are the hallmarks of Alzheimer’s disease (AD). A number of amyloid precursor protein (APP) transgenic (Tg) mice harboring APP mutations have been generated as animal models of AD. These mice successfully display amyloid plaque formation and subsequent tau hyperphosphorylation, but seldom induce NFT formations. We have demonstrated that the APP_OSK-Tg mice, which possess the E693Δ (Osaka) mutation in APP and thereby accumulate Aβ oligomers without plaques, exhibit tau hyperphosphorylation at 8 months, but not NFT formation even at 24 months. We assumed that APP-Tg mice, including ours, failed to form NFTs because NFT formation requires human tau. To test this hypothesis, we crossbred APP_OSK-Tg mice with tau-Tg mice (tau264), which express low levels of 3-repeat and 4-repeat wild-type human tau without any pathology. The resultant double Tg mice displayed tau hyperphosphorylation at 6 months and NFT formation at 18 months in the absence of tau mutations. Importantly, these NFTs contained both 3-repeat and 4-repeat human tau, similar to those in AD. Furthermore, the double Tg mice exhibited Aβ oligomer accumulation, synapse loss, and memory impairment at 6 months and neuronal loss at 18 months, all of which appeared earlier than in the parent APP_OSK-Tg mice. These results suggest that Aβ and human tau synergistically interact to accelerate each other’s pathology, that the presence of human tau is critical for NFT formation, and that Aβ oligomers can induce NFTs in the absence of amyloid plaques.

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Title: Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice
Authors: Tomohiro Umeda
Satomi Maekawa
Tetsuya Kimura
Akihiko Takashima
Takami Tomiyama
Hiroshi Mori
Publication date: 01-05-2014
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1259-1

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Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice

Abstract

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Springer Medicine

Abstract

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Acknowledgement to referees