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

Tautou, M.; Eddarkaoui, S.; Descamps, F.; Larchanche, P.-E.; Dumoulin, M.; Lamarre, C.; Blum, D.; Buee, L.; Melnyk, P.; Sergeant, N.

doi:10.1101/2021.04.02.438175

bioRxiv · 10.1101/2021.04.02.438175

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

Tautou, M.·Eddarkaoui, S.·Descamps, F.·Larchanche, P.-E.·Dumoulin, M.·Lamarre, C.·Blum, D.·Buee, L.·Melnyk, P.·Sergeant, N.

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Abstract

A structure-activity relationship has enabled us to identify two molecules, MAGS02-14 and PEL24-199, sharing a {beta}-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 {beta}-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 {beta}-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 A{beta} and Tau pathologies.

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Tautou, M., Eddarkaoui, S., Descamps, F., Larchanche, P.-E., Dumoulin, M., Lamarre, C., Blum, D., Buee, L., Melnyk, P., Sergeant, N.. 2021-04-02. A β-secretase modulator decreases Tau pathology and preserves short-term memory in a mouse model of neurofibrillary degeneration. https://doi.org/10.1101/2021.04.02.438175

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