IC‐P‐073: A New Biogenic Happ X Htau Mouse Model Shows Progressive Brain Pathology and Behavioral Disturbance

Two hallmarks of AD are amyloid plaques and neurofibrillary tangle pathology. These two were so far not successfully combined in one transgenic mouse model. Progressive amyloid and TAU pathology are described to lead to increased oxidative stress, mitochondrial impairment, inflammatory reactions, cytoskeletal deterioration, apoptosis and finally to loss of synapses and neurons. Crossbreeding of two well characterized transgenic mouse lines of AD, a hAPP over-expression mouse with Swedish and London mutations and a hTAU overexpressor was initiated. The goal was to get further insights whether these two transgenes synergistically induce the occurrence of AD related pathologic alterations and behavioral disturbances. Mice with a C57BL/6 background overexpressing TAU441 with the missense mutations V337M and R406W under the control of the brain specific murine Thy-1 promoter and mice overexpressing human APP carrying the Swedish and London mutations using the same promoter were crossbred. Behavioral changes were investigated at ages of 4, 5 and 6 months followed by evaluation of brain pathology using immunohistochemical staining e.g. with several anti-human PHF-TAU and amyloid antibodies. Furthermore brain inflammatory reaction, number of synapses and neurons were investigated. Evaluation of the cognitive function in the Morris Water Maze (MWM) showed a significant disturbance of the spatial navigation behavior in these mice already at an age of 4 months. Brain TAU pathology revealed numerous densely packed human TAU-positive lesioned neurons. In addition to that the typical amyloid pathology like extracellular beta-amyloid depositions was observed in this age group. The hAPP-SL x hTAU crossbreds were found to effectively simulate AD pathology. The model is expected to be a proper tool to investigate the efficacy of compounds that address the combination of amyloid and TAU pathology as present in humans.