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A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology

The progress in Alzheimer’s disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design...

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Autores principales: Tautou, Marie, Descamps, Florian, Larchanché, Paul-Emmanuel, Buée, Luc, El Bakali, Jamal, Melnyk, Patricia, Sergeant, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048993/
https://www.ncbi.nlm.nih.gov/pubmed/36982363
http://dx.doi.org/10.3390/ijms24065285
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author Tautou, Marie
Descamps, Florian
Larchanché, Paul-Emmanuel
Buée, Luc
El Bakali, Jamal
Melnyk, Patricia
Sergeant, Nicolas
author_facet Tautou, Marie
Descamps, Florian
Larchanché, Paul-Emmanuel
Buée, Luc
El Bakali, Jamal
Melnyk, Patricia
Sergeant, Nicolas
author_sort Tautou, Marie
collection PubMed
description The progress in Alzheimer’s disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive β-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aβ plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aβ plaque load, and inflammatory processes in APP(Swe)/PSEN1(ΔE9) PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process.
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spelling pubmed-100489932023-03-29 A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology Tautou, Marie Descamps, Florian Larchanché, Paul-Emmanuel Buée, Luc El Bakali, Jamal Melnyk, Patricia Sergeant, Nicolas Int J Mol Sci Article The progress in Alzheimer’s disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive β-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aβ plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aβ plaque load, and inflammatory processes in APP(Swe)/PSEN1(ΔE9) PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process. MDPI 2023-03-09 /pmc/articles/PMC10048993/ /pubmed/36982363 http://dx.doi.org/10.3390/ijms24065285 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tautou, Marie
Descamps, Florian
Larchanché, Paul-Emmanuel
Buée, Luc
El Bakali, Jamal
Melnyk, Patricia
Sergeant, Nicolas
A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title_full A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title_fullStr A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title_full_unstemmed A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title_short A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APP(Swe)/PSEN1(ΔE9) Mice Model of Amyloid Pathology
title_sort polyaminobiaryl-based β-secretase modulator alleviates cognitive impairments, amyloid load, astrogliosis, and neuroinflammation in app(swe)/psen1(δe9) mice model of amyloid pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048993/
https://www.ncbi.nlm.nih.gov/pubmed/36982363
http://dx.doi.org/10.3390/ijms24065285
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