A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2021

A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration

Marie Tautou
  • Fonction : Auteur
Sabiha Eddarkaoui
  • Fonction : Auteur
Florian Descamps
  • Fonction : Auteur
Paul-Emmanuel Larchanché
  • Fonction : Auteur
Mélanie Dumoulin
  • Fonction : Auteur
Chloé Lamarre
  • Fonction : Auteur
Luc Buée
Patricia Melnyk
Nicolas Sergeant
  • Fonction : Auteur

Résumé

Abstract 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.

Dates et versions

hal-03203349 , version 1 (20-04-2021)

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Marie Tautou, Sabiha Eddarkaoui, Florian Descamps, Paul-Emmanuel Larchanché, Mélanie Dumoulin, et al.. A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration. 2021. ⟨hal-03203349⟩

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