A novel AD model mouse displaying NFT formation

Tomohiro Umeda

Department of Neuroscience, Osaka City University Graduate School of Medicine

A number of amyloid precursor protein (APP) transgenic (Tg) mice harboring APP mutations have been generated as Alzheimer's disease (AD) models. These mice display amyloid pathology and tau hyperphosphorylation, but seldom induce NFT formation. We assumed that NFT formation requires human tau. To test this hypothesis, we crossbred APPOSK-Tg mice, which possess the Osaka mutation in APP and thereby accumulate Aβ oligomers at 8 months, with Tau264 mice, which express 3-repeat and 4-repeat wild-type human tau without any pathology. The resultant double Tg mice displayed NFT formation at 18 months. These NFTs contained both 3-repeat and 4-repeat human tau, similar to AD. Furthermore, the double Tg mice exhibited Aβ oligomer accumulation, tau hyperphosphorylation, 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 Aβ and tau synergistically interact to accelerate each other's pathology, and that the presence of human tau is critical for NFT formation.

Address correspondence to Dr. Tomohiro Umeda, Department of Neuroscience, Osaka City University Graduate School of Medicine (1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan)