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

Abstract

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.

The Neuronal Expression of MYC Causes a Neurodegenerative Phenotype in a Novel Transgenic Mouse

“…Importantly, our CaMKII-MYC mice preclude initial and developmentally specific consequences of oncogene expression and hence represent a valuable model for studying the pathogenesis of age-related neurodegenerative diseases. In contrast to other approaches for induction of cell cycle re-entry in neurons such as the SV40 T antigen, 16 MYC is a physiologically relevant entity that has been shown to be increased in vulnerable neurons in patients with AD. 20 Like our studies, this ADrelated expression of MYC is restricted to increases in specific neuronal populations, dystrophic neurites, and neurofibrillary tangles without global increases in expression by immunoblot.…”

“…28 Although these data are consistent with our conclusion that cell cycle reactivation in neurons leads to neurodegeneration, the effect of the SV40 T antigen and dysregulation of cell cycle re-entry during development cannot be excluded in those studies. Furthermore, although a new inducible SV40 T antigen transgenic model was recently developed 16 to avoid those problems, SV40 T antigen is not a physiologically relevant entity in neurodegenerative disease and further study is required to delineate its exact mechanism of action. Importantly, our CaMKII-MYC mice preclude initial and developmentally specific consequences of oncogene expression and hence represent a valuable model for studying the pathogenesis of age-related neurodegenerative diseases.…”

“…Furthermore, in traditional transgenic mouse models, 15 the expression of transgenes during embryogenesis, which results in neurodegeneration at an early age, is more akin to a developmental error than an age-dependent process associated with neurodegenerative disease. Although a recently developed inducible SV40 T-antigen transgenic model 16 addressed such developmental issues, SV40 T antigen is not a physiologically relevant entity in any neurodegenerative disease. As such, a faithful and physiologically relevant model of neuronal cell cycle activation in mature neurons was lacking.…”

Tau protein aggregation is associated with cellular senescence in the brain

“…The upstream mediators driving tau‐associated cellular senescence in AD and PSP also remain unknown; however, it is tempting to speculate that tau‐induced cell cycle re‐entry may be involved (Arendt, 2012). Aberrant cell cycle re‐entry causes neuronal apoptosis and AD‐associated pathology (Park, Hallows, Chakrabarty, Davies, & Vincent, 2007) and requires soluble tau (Seward et al, 2013). The observed increase in NFT‐associated Cdkn1a and Cdkn2a gene expression may allow stressed neurons to abort cell cycle re‐entry and enter a cellular state similar to cellular senescence.…”

Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models

“…Predictably, these mice do not develop Aβ plaques. The development of both Aβ plaques and NFTs has been achieved recently in a "triple transgenic" mouse expressing APP, PS1, and the mutant tau protein, and also with conditional expression neuronal expression of SV40 T antigen [55].…”