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A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

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.
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https://www.hal.inserm.fr/inserm-03366685
Contributor : Luc Buee Connect in order to contact the contributor
Submitted on : Tuesday, October 5, 2021 - 5:41:31 PM
Last modification on : Wednesday, October 20, 2021 - 12:03:20 PM

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Marie Tautou, Sabiha Eddarkaoui, Florian Descamps, Paul-Emmanuel Larchanché, Jamal El Bakali, et al.. A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration. Frontiers in Pharmacology, Frontiers, 2021, 12, pp.679335. ⟨10.3389/fphar.2021.679335⟩. ⟨inserm-03366685⟩

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