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: 3.23). 05/2002; 446(3):257-66. DOI: 10.1002/cne.10186
Source: PubMed


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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    • "Importantly, transgenic models expressing human tau are capable of reproducing NFT formation [21,22]. In contrast, genetic models lacking human tau expression such as p25-transgenic mice, which overexpress the human activator of CDK5 kinase, [23,24] and chemical-induced models [25,26] lead to hyperphosphorylated tau in brain regions rich in tau expression, but not to NFT formation (for review of tau rodent models see "
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    ABSTRACT: Hypherphosphorylation of the tau protein leading to the formation of neurofibrillary tangles (NFTs) is a common feature in a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD) and the frontotemporal dementias (FTDs). Although heavily investigated, the mechanisms underlying the pathogenesis and progression of tauopathies has yet to be fully understood. In this context, several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology, aiming to achieve a better understanding of the link between tau and neurodegeneration. To date, behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid (CSF) sampling or post-mortem analysis. Recently, several novel positron emission tomography (PET) radiopharmaceuticals targeting tau tangles have been developed, allowing for non-invasive in vivo quantification of tau pathology. Combined with tau transgenic models and microPET, these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies. In this review, we briefly describe some of the most important insights for understanding the biological basis of tau pathology, and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.
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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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    • "Transgenic expression of p25 induces hyperphosphorylation of tau (Ahlijanian et al., 2000; Bian et al., 2002), with some models also showing induced progressive neurodegeneration and neurofibrillary tangle pathology (Cruz et al., 2003), adding further support to its role in AD pathogenesis. Because there is currently no available transgenic mouse model of TTBK1 or TTBK2 to study their roles in brain pathologies , we have created transgenic mice (TTBK1-Tg) harboring 57kb human TTBK1 genomic DNA derived from P1-derived artificial chromosome (PAC) clone to reconstitute physiological expression pattern of human TTBK1 gene in mice. "
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