Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau
The rTg4510 mouse is a tauopathy model, characterized by massive neurodegeneration in Alzheimer’s disease (AD)-relevant cortical and limbic structures, deficits in spatial reference memory, and progression of neurofibrillary tangles (NFT). In this study, we examined the role of apoptosis in neuronal loss and associated tau pathology. The results showed that DNA fragmentation and caspase-3 activation are common in the hippocampus and frontal cortex of young rTg4510 mice. These changes were associated with cleavage of tau into smaller intermediate fragments, which persist with age. Interestingly, active caspase-3 was often co-localized with cleaved tau. In vitro, fibrillar Aβ1–42 resulted in nuclear fragmentation, caspase activation, and caspase-3-induced cleavage of tau. Notably, incubation with the antiapoptotic molecule tauroursodeoxycholic acid abrogated apoptosis-mediated cleavage of tau in rat cortical neurons. In conclusion, caspase-3-cleaved intermediate tau species occurred early in rTg54510 brains and preceded cell loss in Aβ-exposed cultured neurons. These results suggest a potential role of apoptosis in neurodegeneration.
We are grateful to Karen H Ashe, University of Minnesota; Minneapolis, Minnesota, United States of America for providing the rTg4510 mice. This work was supported in part by grants POCI/SAU-MMO/57936/2004 and PTDC/SAU-FCF/67912/2006 from Fundação para a Ciência e Tecnologia (FCT), Lisbon, Portugal. R.M.R and R.S.V. were recipients of Ph.D. fellowships (SFRH/BD/12641/ 2003 and SFRH/BD/30467/2006, respectively), and R.E.C. was recipient of Postdoctoral fellowship (SFRH/BPD/30257/ 2006) from FCT.
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