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The Journal of Neuroscience, March 14, 2007, 27(11):2969-2978; doi:10.1523/JNEUROSCI.0186-07.2007

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Neurobiology of Disease
Conditional Neuronal Simian Virus 40 T Antigen Expression Induces Alzheimer-Like Tau and Amyloid Pathology in Mice

Kevin H. J. Park,¹ Janice L. Hallows,¹ Paramita Chakrabarty,² Peter Davies,³ and Inez Vincent¹

¹Centre for Molecular Medicine and Therapeutics, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4, ²Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, and ³Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to Dr. Inez Vincent, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4. Email: ivincent{at}cmmt.ubc.ca

A large body of evidence has shown the activation of a cohort of cell cycle regulators and the duplication of DNA in degenerating neurons of Alzheimer's disease (AD) brain. Activation of these regulators and duplication of chromosomes precede neurodegeneration and formation of neurofibrillary tangles (NFTs), one of the diagnostic lesions of AD. These findings, in combination with evidence for cell cycle regulation of amyloid precursor protein and tau, has led to the hypothesis that reentry into the cell cycle underlies AD pathogenesis. To test this hypothesis directly, we have created transgenic mice with forced cell cycle activation in postmitotic neurons via conditional expression of the simian virus 40 large T antigen (TAg) oncogene. We show that TAg mice recapitulate the cell cycle changes seen in AD and display a neurodegenerative phenotype accompanied by tau pathology and NFT-like profiles. Moreover, plaque-like amyloid deposits, similar to those seen in AD, are also observed in the brains of TAg mice. These data provide support for an essential role of ectopic cell cycle activation in the generation of the characteristic pathological hallmarks of AD. Furthermore, our TAg mice are the first model to develop NFTs and amyloid pathology simultaneously and in the absence of any human transgenes. These mice will be useful for further defining the nongenetic mechanisms in AD pathogenesis and for the development of cell cycle-based therapies for AD.

Key words: Alzheimer's disease; cell cycle; SV40 T antigen; amyloid plaque; neurofibrillary tangle; transgenic mice

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Received Sept. 18, 2006; revised Feb. 6, 2007; accepted Feb. 8, 2007.

Correspondence should be addressed to Dr. Inez Vincent, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4. Email: ivincent{at}cmmt.ubc.ca

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