TY - JOUR T1 - A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration JF - bioRxiv DO - 10.1101/2021.04.02.438175 SP - 2021.04.02.438175 AU - Marie Tautou AU - Sabiha Eddarkaoui AU - Florian Descamps AU - Paul-Emmanuel Larchanché AU - Mélanie Dumoulin AU - Chloé Lamarre AU - David Blum AU - Luc Buée AU - Patricia Melnyk AU - Nicolas Sergeant Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/02/2021.04.02.438175.abstract N2 - A structure-activity relationship has enabled us to identify two molecules, MAGS02-14 and PEL24-199, sharing a β-secretase modulatory effect but having or not a lysosomotropic activity, respectively. More importantly, MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. However, which of the lysosomotropic and/or β-secretase modulating activities is necessary for the pharmacological effect in vivo remains ill-defined. To address this question, the THY-Tau22 transgenic model of NFD was treated for 6 weeks in a curative paradigm and short-term memory, Tau burden, and inflammatory processes were studied. PEL24-199, possessing only the β-secretase modulatory activity, was shown to restore the short-term memory and to reduce NFD. This effect was associated with reduced phosphorylation of Tau, increased phosphatase expression, and a decrease of astrogliosis. Our results therefore suggest that the lysosomotropic activity may be dispensable for the effect on both Aβ and Tau pathologies.Competing Interest StatementThe authors have declared no competing interest. ER -