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Somatic Gene Transfer Using a Recombinant Adenoviral Vector (rAAV9) Encoding Pseudophosphorylated Human Thr(175) Tau in Adult Rat Hippocampus Induces Tau Pathology

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Journal of Neurpathology and Experimental Neurology



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Aberrant phosphorylation of the microtubule associated protein tau (tau) is associated with multiple neurodegenerative diseases where it is a contributes to neurotoxicity. We have observed that phosphorylation at Thr(175) tau (pThr(175) tau) exerts toxicity when expressed as a pseudophosphorylated tau construct (Thr(175) Asp) in vitro. To determine whether pThr(175) tau can induce tau pathology in vivo with an accompanying clinical phenotype, we used a recombinant adenoviral expression vector (rAAV9) to express a GFP-tagged Thr(175) Asp tau protein construct in adult female Sprague-Dawley rat hippocampus. Ten rats per group were injected with rAAV9 vectors encoding either GFP, wild type GFP-tagged tau protein, Thr(175) Ala tau or Thr(175) Asp tau. 12 months postinjection, all rats were investigated by immunohistochemistry for GFP (extent of vector expression), pThr(231) tau protein, activated GSK3 beta, and caspase-3 cleavage. Vector expression was primarily localized to hippocampal CA2 subregion. Tau protein pathology restricted to the CA2 region in the form of axonal beading, fibrils, and neurofibrillary tangles was observed in Thr(175) Asp tau inoculated brains and included colocalization with pThr(231) tau and caspase-3 cleavage in this group only. Although no behavioral or imaging phenotype was observed, our results demonstrate that pThr(175) tau protein is capable of exerting neuronal toxicity in vivo.

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