P4‐474: CHARACTERIZATION OF A NOVEL HUMANIZED WILD‐TYPE TAU EXPRESSING MOUSE MODEL IN HIGH‐AMYLOID BACKGROUND OF 5XFAD MICE

Translation of novel therapies against Alzheimer's Disease (AD) into human patients has proven to be challenging, even though preclinical studies in mice frequently showed a disease modifying effect. Therefore, current mouse models are not fully representative for human AD pathology. Here, we have generated a human wild-type tau knock-in model by whole gene replacement and characterized these mice in the high-amyloid background of 5xFAD mice. The htau-KI mouse model was cross-bred with the 5xFAD mouse model, which shows severe AD-related neuropathology and behavioral deficits starting at an age of 6 months. The analysis comprised an extensive phenotyping battery, histopathological, biochemical and electrophysiological methods. In addition, gene expression is planned to be studied by qPCR and a Nanostring panel until June 2019. Phenotyping was performed at the ages of 6 and 12 months, of both genders. The htau-KI mice showed normal cognitive performance, similar to wild types. The 5xFADxhtau-KI mice displayed cognitive deficits in Morris water maze, and decreased anxiety in elevated plus maze, similar to 5xFAD mice. Furthermore, electrophysiology was performed on 7–8 months old mice and showed LTP deficits in htau-KI and 5xFAD mice compared to wild types. Interestingly, a sex-specific rescue of LTP in 5xFADxhtau-KI males was found, while LTP was also impaired in 5xFADxhtau-KI females. Further characterization of neuropathology, using both immunohistochemistry and western blot, is currently underway. Here, only selected pathological markers of tau phosphorylation are present in 5xFADxhtau-KI mice. PHF-tau seems to be absent in these mice. Cognitive deficits in 5xFAD x htau-KI are induced by high-amyloid load of the 5xFAD background. In contrast, htau-KI seems to rescue the LTP deficit in 5xFAD in a gender-specific manner. The absence of tangle-pathology again argues against a direct induction of tau pathology solely by high-amyloid load.