A ss-Secretase Modulator Decreases Tau ...
Document type :
Article dans une revue scientifique: Article original
PMID :
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Title :
A ss-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration
Author(s) :
Tautou, Marie [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Eddarkaoui, Sabiha [Auteur]
Excellence Laboratory LabEx DISTALZ
Lille Neurosciences & Cognition (LilNCog) - U 1172
Descamps, Florian [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Larchanche, Paul-Emmanuel [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
El Bakali, Jamal [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Goveas, Liesel Mary [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Dumoulin, Mélanie [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Lamarre, Chloé [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Blum, David [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Buee, Luc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Melnyk, Patricia [Auteur]
Excellence Laboratory LabEx DISTALZ
Lille Neurosciences & Cognition (LilNCog) - U 1172
Sergeant, Nicolas [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Eddarkaoui, Sabiha [Auteur]
Excellence Laboratory LabEx DISTALZ
Lille Neurosciences & Cognition (LilNCog) - U 1172
Descamps, Florian [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Larchanche, Paul-Emmanuel [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
El Bakali, Jamal [Auteur]

Lille Neurosciences & Cognition (LilNCog) - U 1172
Goveas, Liesel Mary [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Dumoulin, Mélanie [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Lamarre, Chloé [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Blum, David [Auteur]

Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Buee, Luc [Auteur]

Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Melnyk, Patricia [Auteur]

Excellence Laboratory LabEx DISTALZ
Lille Neurosciences & Cognition (LilNCog) - U 1172
Sergeant, Nicolas [Auteur]

Lille Neurosciences & Cognition (LilNCog) - U 1172
Excellence Laboratory LabEx DISTALZ
Journal title :
Frontiers in Pharmacology
Volume number :
12
Publication date :
2021-06-29
ISSN :
1663-9812
Keyword(s) :
Alzheimer's disease
BACE protein
lysosomes
proteostasis
tauopathy
tau pathology
BACE protein
lysosomes
proteostasis
tauopathy
tau pathology
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Submission date :
2024-01-16T01:59:22Z
2024-11-25T13:37:03Z
2024-11-25T13:37:03Z
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