First transgenic rat model developing progressive cortical neurofibrillary tangles

Institute of Neuroimmunology, Slovak Academy of Sciences, Centre of Excellence for Alzheimer's Disease and Related Disorders, Bratislava, Slovak Republic.
Neurobiology of aging (Impact Factor: 5.01). 12/2010; 33(7):1448-56. DOI: 10.1016/j.neurobiolaging.2010.10.015
Source: PubMed


Neurofibrillary degeneration induced by misfolded protein tau is considered to be one of the key pathological hallmarks of Alzheimer's disease (AD). In the present study, we have introduced a novel transgenic rat model expressing a human truncated tau that encompasses 3 microtubule binding domains (3R) and a proline-rich region (3R tau151-391). The transgenic rats developed progressive age-dependent neurofibrillary degeneration in the cortical brain areas. Neurofibrillary tangles (NFTs) satisfied several key histological criteria used to identify neurofibrillary degeneration in human Alzheimer's disease including argyrophilia, Congo red birefringence, and Thioflavin S reactivity. Neurofibrillary tangles were also identified with antibodies used to detect pathologic tau in the human brain, including DC11, recognizing an abnormal tau conformation and antibodies that are specific for hyperphosphorylated forms of tau protein. Moreover, neurofibrillary degeneration was characterized by extensive formation of sarkosyl insoluble tau protein complexes consisting of rat endogenous and truncated tau species. Interestingly, the transgenic rats did not show neuronal loss either in the cortex or in the hippocampus. We suggest that novel transgenic rat model for human tauopathy represents a valuable tool in preclinical drug discovery targeting neurofibrillary degeneration of Alzheimer's type.

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Available from: Norbert Zilka, Sep 18, 2015
    • "It is more likely that monomeric and/or oligomeric intermediates could play a more significant role at the onset of the diseases (Kovacech et al. 2009). Animal models show that transgenic expression of pathological form of human tau protein results in irreversible changes in brain and premature death of the experimental animals (Zilka et al. 2006; Filipcik et al. 2012). In PD, the accumulation of α-synuclein results in formation of Lewy bodies (Goedert et al. 2013). "
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    • "Heterozygous transgenic male rats expressing human N-and Cterminally truncated tau encompassing three repeats (aa 151–391; line SHR24; Filipcik et al., 2012) and age matched wild type rats were used in this study. Rats were housed in cages with adequate supply of water, and 12 h day/light cycle. "
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    ABSTRACT: Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre-and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.
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    • "Furthermore, tau truncation is crucial in formation of neurofibrillary tangles which enables tau assembly into paired helical filaments that leads to AD pathology [40] [41] [42] [43]. Proof of this concept was provided by transgenic AD animal models expressing truncated tau protein (151-391, both 3R and 4R) in rat brain [41] [44]. Expression of truncated tau resulted in neurofibrillary degeneration as found in humans, including paired helical filament formation, increased oxidative stress [45], and neuroinflammation [46]. "
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