@ARTICLE{10.3389/fphar.2021.679335, AUTHOR={Tautou, Marie and Eddarkaoui, Sabiha and Descamps, Florian and Larchanché, Paul-Emmanuel and El Bakali, Jamal and Goveas, Liesel Mary and Dumoulin, Mélanie and Lamarre, Chloé and Blum, David and Buée, Luc and Melnyk, Patricia and Sergeant, Nicolas}, TITLE={A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration}, JOURNAL={Frontiers in Pharmacology}, VOLUME={12}, YEAR={2021}, URL={https://www.frontiersin.org/articles/10.3389/fphar.2021.679335}, DOI={10.3389/fphar.2021.679335}, ISSN={1663-9812}, ABSTRACT={Identifying which among several in cellulo pharmacological activities is necessary for the proper in vivo activity is essential for further drug development against Alzheimer’s disease pathophysiological processes. An in-depth structure–activity relationship–based study has been carried out, and two molecules, named MAGS02-14 and PEL24-199, that share a ß-secretase modulatory effect associated or not to a lysosomotropic activity in cellulo have been identified. In terms of chemical formulas, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. The study aimed to elucidate the in vivo pharmacological effects of lysosomotropic and/or the ß-secretase modulatory activity in a tau pathology mouse model. To address this question, the THY-Tau22 transgenic model of tauopathy was treated with both compounds for 6 weeks in a curative paradigm. Short-term memory, tau burden, and inflammatory processes were analyzed using orthogonal methods, and PEL24-199, but not MAGS02-14, was shown to restore the short-term memory and reduce the neurofibrillary degenerating process. These effects were associated with a reduced phosphorylation of tau, an increased phosphatase expression, and decreased astrogliosis. Our results, therefore, suggest that the lysosomotropic activity may be nonessential for the effect on tau pathology.} }