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Tytuł:
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A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration.
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Autorzy:
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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
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Temat:
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LABORATORY mice
SHORT-term memory
ANIMAL disease models
ALZHEIMER'S disease
CHEMICAL formulas
AMYLOID beta-protein precursor
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Źródło:
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Frontiers in Pharmacology; 6/29/2021, Vol. 12, p1-13, 13p
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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. [ABSTRACT FROM AUTHOR]
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