| First Author | Umeda T | Year | 2014 |
| Journal | Acta Neuropathol | Volume | 127 |
| Issue | 5 | Pages | 685-98 |
| PubMed ID | 24531886 | Mgi Jnum | J:335655 |
| Mgi Id | MGI:7482615 | Doi | 10.1007/s00401-014-1259-1 |
| Citation | Umeda T, et al. (2014) Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol 127(5):685-98 |
| abstractText | Senile plaques comprised of Abeta 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 APPOSK-Tg mice, which possess the E693Delta (Osaka) mutation in APP and thereby accumulate Abeta 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 APPOSK-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 Abeta 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 APPOSK-Tg mice. These results suggest that Abeta and human tau synergistically interact to accelerate each other's pathology, that the presence of human tau is critical for NFT formation, and that Abeta oligomers can induce NFTs in the absence of amyloid plaques. |
