Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load

Koson, Peter; Žilka, Norbert; Kováč, Andrej; Kováčech, Branislav; Korenova, Miroslava; Filipčík, Peter; Novák, Michal

doi:10.1111/j.1460-9568.2008.06329.x

Cited by 70 publications

(61 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These neurons have accumulated large quantities of truncated and hyperphosphorylated tau in the neuronal processes. This finding is consistent with previously published data obtained from in vivo experiments (Koson et al 2008). It will be important to determine whether or not the interneuronal connectivity is compromised in such old cultures.…”

Section: Discussionsupporting

confidence: 95%

Cortical and Hippocampal Neurons from Truncated Tau Transgenic Rat Express Multiple Markers of Neurodegeneration

et al. 2009

Self Cite

View full text Add to dashboard Cite

Transition of protein tau from physiologically unfolded to misfolded state represent enigmatic step in the pathogenesis of tauopathies including Alzheimer's disease (AD). Major molecular events playing role in this process involve truncation and hyperphosphorylation of tau protein, which are accompanied by redox imbalance followed by functional deterioration of neuronal network. Recently we have developed transgenic rat model showing that expression of truncated tau causes neurofibrillary degeneration similar to that observed in brain of AD sufferers. Consequently we tested cortical and hippocampal neuronal cultures extracted from this model as a convenient tool for development of molecules able to target the mechanisms leading to and/or enhancing the process of neurodegeneration. Here we document three major pathological features typical for tauopathies and AD in cortical and hippocampal neurons from transgenic rat in vitro. First, an increased accumulation of human truncated tau in neurons; second, the hyperphosphorylation of truncated tau on the epitopes characteristic of AD (Ser202/Thr205 and Thr231); and third, increased vulnerability of the neurons to nitrative and oxidative stress. Our results show that primary neurons expressing human truncated tau could represent a cellular model for targeting tau related pathological events, namely, aberrant tau protein accumulation, tau hyperphosphorylation, and oxidative/nitrative damage. These characteristics make the model particularly suitable for detailed study of molecular mechanisms of tau induced neurodegeneration and easily applicable for drug screening.

show abstract

Section: Discussionsupporting

confidence: 95%

Cortical and Hippocampal Neurons from Truncated Tau Transgenic Rat Express Multiple Markers of Neurodegeneration

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this study, we focused on truncated t protein, which has been shown to be a driving force behind neurofibrillary degeneration in transgenic rats expressing misfolded truncated t (44,45). We have previously demonstrated that in the transgenic rat brain, neurofibrillary lesions and axonal degeneration are closely associated with the distribution of reactive microglia and macrophages (40).…”

Section: Human Truncated T Stimulates Activation Of Microglia Throughmentioning

confidence: 99%

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Kováč

Žilka

Kazmerova

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Neuroinflammation plays a key role in the pathogenesis of Alzheimer’s disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer’s disease.

show abstract

“…The model expressing non-mutated truncated tau derived from sporadic Alzheimer's disease displayed the ADcharacteristic tau cascade consisting of argyrophilic and phospho-tau positive neurofibrillary tangles, mature sarcosyl insoluble tau complexes and extensive axonal damage in the brain stem and spinal cord. Surprisingly, transgene expression does not cause neuronal loss in the transgenic rat brain (Koson et al 2008). Axonopathy led to neurogenic muscular atrophy, which was the primary cause of progressive muscle weakness.…”

Section: The Rat Models For Human Neurodegenerative Disordersmentioning

confidence: 98%

Beyond the Rat Models of Human Neurodegenerative Disorders

2009

Self Cite

View full text Add to dashboard Cite

The rat is a model of choice in biomedical research for over a century. Currently, the rat presents the best "functionally" characterized mammalian model system. Despite this fact, the transgenic rats have lagged behind the transgenic mice as an experimental model of human neurodegenerative disorders. The number of transgenic rat models recapitulating key pathological hallmarks of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or human tauopathies is still limited. The reason is that the transgenic rats remain more difficult to produce than transgenic mice. The gene targeting technology is not yet established in rats due to the lack of truly totipotent embryonic stem cells and cloning technology. This extremely powerful technique has given the mouse a clear advantage over the rat in generation of new transgenic models. Despite these limitations, transgenic rats have greatly expanded the range of potential experimental approaches. The large size of rats permits intrathecal administration of drugs, stem cell transplantation, serial sampling of the cerebrospinal fluid, microsurgical techniques, in vivo nerve recordings, and neuroimaging procedures. Moreover, the rat is routinely employed to demonstrate therapeutic efficacy and to assess toxicity of novel therapeutic compounds in drug development. Here we suggest that the rat constitutes a slightly underestimated but perspective animal model well-suited for understanding the mechanisms and pathways underlying the human neurodegenerative disorders.

show abstract

Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load

Cited by 70 publications

References 34 publications

Cortical and Hippocampal Neurons from Truncated Tau Transgenic Rat Express Multiple Markers of Neurodegeneration

Cortical and Hippocampal Neurons from Truncated Tau Transgenic Rat Express Multiple Markers of Neurodegeneration

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Beyond the Rat Models of Human Neurodegenerative Disorders

Contact Info

Product

Resources

About