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, Aug 05, 2015
- SourceAvailable from: Erwin Swinnen
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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.04/2011; 2011:428970. 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 · 3.51 Impact Factor
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- "Staggering gait after 1 year of age  Knockout Progressive muscle weakness KIF5A knockout NF accumulations especially in sensory neurons  Degeneration of sensory axons but not of motor axons after 5 months Dynein mutations heterozygous Progressive motor dysfunction  Loss of 4 to 70% of motor neurons at 16 months pmn mouse Axonal swellings and early-onset motor neuron degeneration   Short tau overexpressor Spheroidal inclusions containing tau, NFs and tubulin  20% loss of motor axons at 12 months P25 overexpressor Abnormal tau phosphorylation and axonopathy  Others VEGF ΔHRE Late-onset motor dysfunction  Loss of 40% motor axons at 7 months Als2 knockout Late-onset degeneration of cerebellar Purkinje cells   been detected at early stages of disease in mice expressing mutant SOD1  . Many transgenic mice have been generated in which ALSlinked SOD1 mutants of different biochemical properties were expressed. "
ABSTRACT: The discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial cases was rapidly followed by the generation of transgenic mice expressing various forms of SOD1 mutants. The mice overexpressing high levels of mutant SOD1 mRNAs do develop motor neuron disease but unraveling the mechanisms of pathogenesis has been very challenging. Studies with mouse lines suggest that the toxicity of mutant SOD1 is unrelated to copper-mediated catalysis but rather to propensity of a subfraction of mutant SOD1 proteins to form misfolded protein species and aggregates. However, the mechanism of toxicity of SOD1 mutants remains to be elucidated. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Here, we describe how transgenic mouse models have been used for understanding pathogenic pathways of motor neuron disease and for pre-clinical drug testing.Biochimica et Biophysica Acta 12/2006; 1762(11-12):1013-24. DOI:10.1016/j.bbadis.2006.03.006 · 4.66 Impact Factor