Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice

CNS Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
The Journal of Comparative Neurology (Impact Factor: 3.51). 05/2002; 446(3):257-66. DOI: 10.1002/cne.10186
Source: PubMed

ABSTRACT Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.

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Available from: Kevin KW Wang, Aug 05, 2015
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    • "Tau is a proven Cdk5 target in vivo [92] and in vitro, it was shown that phosphorylation by Cdk5 promotes tau dimerization [104]. Activation of Cdk5, by overexpressing its activator p25, accelerates tau phosphorylation and aggregation in mice overexpressing mutant P301L tau [105], and has even been shown to contribute to tau pathology in mice expressing only endogenous tau [106] [107]. Of interest, Cdk5 activity is elevated in the prefrontal cortex of AD brain, where NFT are found, but not in the cerebellar cortex, suggesting a relationship between deregulated Cdk5 activity and tau pathology in humans [108] [109]. "
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    • "Interestingly, they were not significantly impaired in ingestion and aged to at least 14 months. Neuropathological analysis showed phosphotau-positive ovoid structures mostly located in white matter pathways as well as numerous dilated axons in the corpus callosum identified by means of electron microscopy (Bian et al. 2002). Similar axonal dilatations have been previously reported on the ultrastructural level in the amygdala and spinal cord of another p25 transgenic mouse model (Ahlijanian et al. 2000). "
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