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The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models

Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indi...

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Autores principales: Bécot, Anaïs, Pardossi-Piquard, Raphaëlle, Bourgeois, Alexandre, Duplan, Eric, Xiao, Qingli, Diwan, Abhinav, Lee, Jin-Moo, Lauritzen, Inger, Checler, Frédéric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291113/
https://www.ncbi.nlm.nih.gov/pubmed/32408680
http://dx.doi.org/10.3390/cells9051204
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author Bécot, Anaïs
Pardossi-Piquard, Raphaëlle
Bourgeois, Alexandre
Duplan, Eric
Xiao, Qingli
Diwan, Abhinav
Lee, Jin-Moo
Lauritzen, Inger
Checler, Frédéric
author_facet Bécot, Anaïs
Pardossi-Piquard, Raphaëlle
Bourgeois, Alexandre
Duplan, Eric
Xiao, Qingli
Diwan, Abhinav
Lee, Jin-Moo
Lauritzen, Inger
Checler, Frédéric
author_sort Bécot, Anaïs
collection PubMed
description Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.
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spelling pubmed-72911132020-06-17 The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models Bécot, Anaïs Pardossi-Piquard, Raphaëlle Bourgeois, Alexandre Duplan, Eric Xiao, Qingli Diwan, Abhinav Lee, Jin-Moo Lauritzen, Inger Checler, Frédéric Cells Article Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite. MDPI 2020-05-12 /pmc/articles/PMC7291113/ /pubmed/32408680 http://dx.doi.org/10.3390/cells9051204 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bécot, Anaïs
Pardossi-Piquard, Raphaëlle
Bourgeois, Alexandre
Duplan, Eric
Xiao, Qingli
Diwan, Abhinav
Lee, Jin-Moo
Lauritzen, Inger
Checler, Frédéric
The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title_full The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title_fullStr The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title_full_unstemmed The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title_short The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models
title_sort transcription factor eb reduces the intraneuronal accumulation of the beta-secretase-derived app fragment c99 in cellular and mouse alzheimer’s disease models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291113/
https://www.ncbi.nlm.nih.gov/pubmed/32408680
http://dx.doi.org/10.3390/cells9051204
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