Cargando…

Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction

The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These...

Descripción completa

Detalles Bibliográficos
Autores principales: Benito-Cuesta, Irene, Ordoñez-Gutierrez, Lara, Wandosell, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306653/
https://www.ncbi.nlm.nih.gov/pubmed/34206776
http://dx.doi.org/10.3390/metabo11070421
_version_ 1783727862383116288
author Benito-Cuesta, Irene
Ordoñez-Gutierrez, Lara
Wandosell, Francisco
author_facet Benito-Cuesta, Irene
Ordoñez-Gutierrez, Lara
Wandosell, Francisco
author_sort Benito-Cuesta, Irene
collection PubMed
description The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer’s disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aβ) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aβ levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aβ precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate.
format Online
Article
Text
id pubmed-8306653
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83066532021-07-25 Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction Benito-Cuesta, Irene Ordoñez-Gutierrez, Lara Wandosell, Francisco Metabolites Article The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer’s disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aβ) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aβ levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aβ precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate. MDPI 2021-06-26 /pmc/articles/PMC8306653/ /pubmed/34206776 http://dx.doi.org/10.3390/metabo11070421 Text en © 2021 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
Benito-Cuesta, Irene
Ordoñez-Gutierrez, Lara
Wandosell, Francisco
Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title_full Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title_fullStr Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title_full_unstemmed Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title_short Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction
title_sort trehalose reduces the secreted beta-amyloid levels in primary neurons independently of autophagy induction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306653/
https://www.ncbi.nlm.nih.gov/pubmed/34206776
http://dx.doi.org/10.3390/metabo11070421
work_keys_str_mv AT benitocuestairene trehalosereducesthesecretedbetaamyloidlevelsinprimaryneuronsindependentlyofautophagyinduction
AT ordonezgutierrezlara trehalosereducesthesecretedbetaamyloidlevelsinprimaryneuronsindependentlyofautophagyinduction
AT wandosellfrancisco trehalosereducesthesecretedbetaamyloidlevelsinprimaryneuronsindependentlyofautophagyinduction