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 http://www.alzforum.org/research-models). "
[Show abstract][Hide abstract] 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.
Full-text · Article · Mar 2014 · Translational Neurodegeneration
"Tau is a proven Cdk5 target in vivo  and in vitro, it was shown that phosphorylation by Cdk5 promotes tau dimerization . Activation of Cdk5, by overexpressing its activator p25, accelerates tau phosphorylation and aggregation in mice overexpressing mutant P301L tau , and has even been shown to contribute to tau pathology in mice expressing only endogenous tau  . 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  . "
[Show abstract][Hide abstract] ABSTRACT: Hyperphosphorylated and aggregated human protein tau constitutes a hallmark of a multitude of neurodegenerative diseases called tauopathies, exemplified by Alzheimer's disease. In spite of an enormous amount of research performed on tau biology, several crucial questions concerning the mechanisms of tau toxicity remain unanswered. In this paper we will highlight some of the processes involved in tau biology and pathology, focusing on tau phosphorylation and the interplay with oxidative stress. In addition, we will introduce the development of a human tau-expressing yeast model, and discuss some crucial results obtained in this model, highlighting its potential in the elucidation of cellular processes leading to tau toxicity.
Full-text · Article · Apr 2011 · International Journal of Alzheimer's Disease
"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. "
[Show abstract][Hide abstract] ABSTRACT: Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activation in vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.
Preview · Article · Jan 2009 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience