engleski

Development of non-transgenic rat tauopathy model by application of tau oligomers into the entorhinal cortex

Alzheimer's disease (AD) is the most common secondary tauopathy characterized by progressive loss of cognitive functions and behavioral impairment. The hyperphoshorylation and aggregation of tau proteins progress in a stereotypical manner with the first changes seen in the locus coeruleus and entorhinal cortex from where they spread to the hippocampus and other cortical regions. We aimed to explore whether intracerebral injection of tau oligomers and tau fibrils will induce trans-synaptic spread of pathological tau proteins, adn whether those changes would be associated with cognitive impairment. Four-month-old male Wistar rats (n=96) were stereotaxically injected into the lateral entorhinal cortex with tau oligomers, tau fibrils, and phosphate-buffered saline. Animals were analyzed 4, 8, and 11 months post-injection. Cognitive performance was tested using open field, T-maze task, novel object recognition, and object-location test. To specifically detect tau protein changes and perform staging of tau pathology, we used anti-tau antibodies AT8, T22, and HT7. Immunohistochemistry and immunoblotting of proteins isolated from the entorhinal cortex and hippocampus showed that stereotaxic injection of tau oligomers or tau fibrils into the lateral entorhinal cortex induced phosphorylation of Ser202/Thr205 tau epitope (AT8) as well as HT7-positive (tau aa 159-163) signal present in the brainstem and transentorhinal region. Oligomeric tau was detected with T22 antibody both ipsilaterally and contralaterally to the injection site. Rewarded learning in the T-maze showed slower learning curve with more incorrect choices in rats injected with oligomers and tau fibrils. Thus, this rat model of neurodegeneration has a great potential for revealing mechanisms underlying development and progression of AD and other human tauopathies.

Alzheimer's disease ; animal model ; cognitive impairment ; entorhinal cortex ; tauopathy ; tau proteins

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