P4‐058: A NOVEL TRANSGENIC RAT MODEL THAT PRESENTS PATHOPHYSIOLOGICAL LEVELS OF HUMAN TAU IN CSF, AXONOPATHY, HIPPOCAMPAL NETWORK DISRUPTION, AND COGNITIVE DEFICITS

Le résumé fourni par la source

Current widely used tau transgenic mouse models rely on the supra-physiological expression of a single isoform of human tau harboring a mutation that is not associated with AD. Furthermore, the phenotype of these models is often related to the ectopic pathology in brain regions unaffected in AD. Because of these limitations, the translational validity of these preclinical models to AD is uncertain. To overcome this, we aimed to develop a novel animal model of AD that more accurately represents endogenous human tau protein expression and related pathology. We developed a rat model, hTau rat, that harbors the human MAPT genomic locus through a bacterial artificial chromosome. Expression of tau and p-tau in the brains and CSF of 3, 6, 9, 12 months old hTau rats were assessed using Western blots, SIMOA, ELISA, and immunohistochemistry. Micro- and astrogliosis in hTau rat brains were analyzed by immunohistochemistry. Hippocampal oscillations elicited by high frequency stimulation of the brainstem nucleus pontis oralis were recorded in anesthetized hTau and wild-type rats. Touchscreen operant tasks were employed to assess cognitive functions. In the brain of hTau rat, human tau was expressed at roughly endogenous levels, all six isoforms were found, and pT181 tau species were specifically elevated. Tau was most robustly expressed in cortex, striatum, and hippocampus in the hTau rat brain, and rare axonal dilatations with tau accumulation were observed, consistent with early axonopathy. Microgliosis and astrogliosis were not apparent in the tested age range. In CSF, hTau rats accumulated tau at concentrations observed in humans. hTau rats exhibited disruption in hippocampal network oscillation reminiscent of the disrupted neuronal synchrony observed in AD patients. Moreover, hTau rats showed deficits in the visual discrimination learning paradigm. hTau rats express tau in a pattern and levels closely mimicking humans. hTau rats also exhibit features of neuropathology related to AD including early signs of tau pathology, neuronal network dysfunction, and subtle cognitive deficits. The hTau rat is a novel tau transgenic model that may serve as a translational preclinical model to test pharmacodynamic effects and efficacy of tau-targeted therapies.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.