Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice
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.
Full-textDOI: · Available from: Kevin KW Wang, Sep 26, 2015
- SourceAvailable from: Eduardo R Zimmer
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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). "
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.Translational Neurodegeneration 03/2014; 3(1):6. DOI:10.1186/2047-9158-3-6
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- "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  . "
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.International Journal of Alzheimer's Disease 04/2011; 2011(43):428970. DOI:10.4061/2011/428970
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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). "
ABSTRACT: In this commentary, we accent the accumulating evidence for motor impairment as a common feature of early Alzheimer’s disease (AD) pathology. In addition, we summarize the state of knowledge on this phenotype in experimental mouse models, expressing AD-associated genes like tau or amyloid precursor protein.Genes Brain and Behavior 01/2008; 7(s1):1 - 5. DOI:10.1111/j.1601-183X.2007.00373.x · 3.66 Impact Factor