engleski

Tau protein spreading after injection of tau oligomers into the rat entorhinal cortex

Alzheimer’s disease (AD) is the most common secondary tauopathy characterized by progressive loss of cognitive functions and behavioral impairment. The hyperphosphorylation and aggregation of tau proteins progress in a stereotypical manner with the first changes seen in the entorhinal cortex and locus coeruleus from where they spread to the hippocampus and other cortical regions, respectively. Here, we aimed to explore if intracerebral injection of tau oligomers and tau fibrils will induce trans-synaptic transfer of pathological tau proteins, and will those changes be associated with cognitive decline. Three to four month old male Wistar rats (n = 96) were stereotaxically injected into the lateral entorhinal cortex with tauoligomers, tau fibrils, and phosphate-buffered saline. Animals were analyzed after post-injection interval of 4 months. Cognitive performance was tested using open field, T-maze task, novel object recognition (NORT), and object-location test (OLT). To detect tau protein changes and perform staging of tau pathology, we used anti-tau antibodies AT8, T22, HT7, and PHF1. Possible amyloid changes were assessed using anti-amyloid antibody 4G8. Proteins isolated from the entorhinal cortex and hippocampus were analyzed by immunoblotting. In comparison to the control and the tau oligomer group, rewarded learning in the T-maze showed slower learning curve with more incorrect choices in rats injected with tau fibrils (-25%, p < 0.05). Immunohistochemistry revealed HT7-positive signal in the brainstem and transentorhinal region only in the group injected with tau fibrils. Here, oligomeric tau was found both ipsilaterally and contralaterally to the injection site. In comparison to sections from control animals where no immunoreactivity was observed, the Ser202/Thr205 phosphorylated tau epitope visualized by AT8 antibody showed weak immunoreactivity in both tau fibril and tau oligomer group. The results obtained suggest that stereotaxic injection of tau oligomers or tau fibrils into the lateral entorhinal cortex induces phosphorylation of AT8 epitope of tau in the rat brain at 4-month post-injection. Using antibody HT7, which recognizes human (and not murine) tau, we found a signal present in the brainstem after injection of tau fibrils into the lateral entorhinal cortex. Therefore, we concluded that understanding of the role of tau oligomers and tau fibrils in this rat model of neurodegeneration has a great potential for revealing mechanisms underlying development and progression of AD and other tauopathies in humans.

tau protein ; tau hyperphosphorylation ; Alzheimer's disease ; tauopathy ; experimental model ; entorhinal cortex ; neurofibrillary degeneration ; stereotaxy ; cognitive testing

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