AUTHOR=Tautou Marie , Eddarkaoui Sabiha , Descamps Florian , Larchanché Paul-Emmanuel , El Bakali Jamal , Goveas Liesel Mary , Dumoulin Mélanie , Lamarre Chloé , Blum David , Buée Luc , Melnyk Patricia , 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=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/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 -secretase modulatory effect associated or not to a lysosomotropic activity in cellulo, have been identified. In terms of the chemical formulae MAGS02-14 and PEL24-199 only differ from each other by a single nitrogen atom. The study aims to elucidate the in vivo pharmacological effects of lysosomotropic and/or the beta-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 non-essential for the effect on both Tau pathology.