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T. HANANIA, D. HAVAS, I. MORGANSTERN, E. SABATH, P. KABITZKE, M. MAZZELLA, K. COX, J. BERGER, M. WINDISCH, D. BRUNNER, V. ALEXANDROV

Background:
Neurofibrillary tangles (NFT) are the second hallmark of Alzheimer’s disease (AD) and they are well correlated to disturbances in cognition. The rTg4510 mouse, a model of tauopathy, overexpresses P301L mutant human Tau in the forebrain under control of a tetracycline tansacting element (TET-Off).The mice develop neurobrillary pathology already at an age of 2,5 to 3 months, and show progressive gross brain atrophy and significant neuronal loss in hippocampal structures. The study investigated the effects suppression of transgene expression by doxycycline (Doxy) feeding on complex behavioral readouts and the correlation to changes in brain pathology.

Methods:
Feeding of mice with Doxy (200 ppm) started at an age of 2,5 months and was maintained until an age of 6 m. The proprietary Cube technology was used to document spontaneous behavior, gait, motor function, but also social interaction, day/ night activity and cognition. Effects on NFTs and brain atrophy were measured using quantitative histological methods, the influence on brain inflammation markers was examined using real time PCR.

Results:
Transgene suppression over 2,5 months is decreasing tau expression significantly, resultíng in normalization of T-maze performance, but also modulation of practically all disturbed behavioral features that were investigated using Smart Cube, Neuro Cube and Pheno Cube, including motor function, rearing, hyperactivity and social behavior. Beside the known effects on brain pathology, Doxy also normalizes the expression of different pro-inflammatory markers in the mouse brain, which could be in connection to progressive brain atrophy.

Conclusions:
The data show first time that exposure to Doxy results in at least a partial reversal of the deficits in the rTG4510mice which were recorded using unique, high-trough-put behavioral methods, which correlates to a significant decrease in markers of neuro-inflammation and expected reduction of NFT pathology, indicating that abnormally processed tau protein is essential for these disturbances.

Shutting down transgene expression by Doxy is a useful benchmarking for preclinical treatment trials for drugs addressing tau pathology.