Cargando…

A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta

There is growing recognition regarding the role of intracellular amyloid beta (Aβ) in the Alzheimer’s disease process, which has been linked with aberrant signaling and the disruption of protein degradation mechanisms. Most notably, intraneuronal Aβ likely underlies the oxidative stress and mitochon...

Descripción completa

Detalles Bibliográficos
Autores principales: Hilt, Silvia, Altman, Robin, Kálai, Tamás, Maezawa, Izumi, Gong, Qizhi, Wachsmann-Hogiu, Sebastian, Jin, Lee-Way, Voss, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222334/
https://www.ncbi.nlm.nih.gov/pubmed/30103547
http://dx.doi.org/10.3390/molecules23082010
_version_ 1783369182509793280
author Hilt, Silvia
Altman, Robin
Kálai, Tamás
Maezawa, Izumi
Gong, Qizhi
Wachsmann-Hogiu, Sebastian
Jin, Lee-Way
Voss, John C.
author_facet Hilt, Silvia
Altman, Robin
Kálai, Tamás
Maezawa, Izumi
Gong, Qizhi
Wachsmann-Hogiu, Sebastian
Jin, Lee-Way
Voss, John C.
author_sort Hilt, Silvia
collection PubMed
description There is growing recognition regarding the role of intracellular amyloid beta (Aβ) in the Alzheimer’s disease process, which has been linked with aberrant signaling and the disruption of protein degradation mechanisms. Most notably, intraneuronal Aβ likely underlies the oxidative stress and mitochondrial dysfunction that have been identified as key elements of disease progression. In this study, we employed fluorescence imaging to explore the ability of a bifunctional small molecule to reduce aggregates of intracellular Aβ and attenuate oxidative stress. Structurally, this small molecule is comprised of a nitroxide spin label linked to an amyloidophilic fluorene and is known as spin-labeled fluorene (SLF). The effect of the SLF on intracellular Aβ accumulation and oxidative stress was measured in MC65 cells, a human neuronal cell line with inducible expression of the amyloid precursor protein and in the N2a neuronal cell line treated with exogenous Aβ. Super-resolution microscopy imaging showed SLF decreases the accumulation of intracellular Aβ. Confocal microscopy imaging of MC65 cells treated with a reactive oxygen species (ROS)-sensitive dye demonstrated SLF significantly reduces the intracellular Aβ-induced ROS signal. In order to determine the contributions of the separate SLF moieties to these protective activities, experiments were also carried out on cells with nitroxides lacking the Aβ targeting domain or fluorene derivatives lacking the nitroxide functionality. The findings support a synergistic effect of SLF in counteracting both the conformational toxicity of both endogenous and exogenous Aβ, its promotion of ROS, and Aβ metabolism. Furthermore, these studies demonstrate an intimate link between ROS production and Aβ oligomer formation.
format Online
Article
Text
id pubmed-6222334
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62223342018-11-13 A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta Hilt, Silvia Altman, Robin Kálai, Tamás Maezawa, Izumi Gong, Qizhi Wachsmann-Hogiu, Sebastian Jin, Lee-Way Voss, John C. Molecules Article There is growing recognition regarding the role of intracellular amyloid beta (Aβ) in the Alzheimer’s disease process, which has been linked with aberrant signaling and the disruption of protein degradation mechanisms. Most notably, intraneuronal Aβ likely underlies the oxidative stress and mitochondrial dysfunction that have been identified as key elements of disease progression. In this study, we employed fluorescence imaging to explore the ability of a bifunctional small molecule to reduce aggregates of intracellular Aβ and attenuate oxidative stress. Structurally, this small molecule is comprised of a nitroxide spin label linked to an amyloidophilic fluorene and is known as spin-labeled fluorene (SLF). The effect of the SLF on intracellular Aβ accumulation and oxidative stress was measured in MC65 cells, a human neuronal cell line with inducible expression of the amyloid precursor protein and in the N2a neuronal cell line treated with exogenous Aβ. Super-resolution microscopy imaging showed SLF decreases the accumulation of intracellular Aβ. Confocal microscopy imaging of MC65 cells treated with a reactive oxygen species (ROS)-sensitive dye demonstrated SLF significantly reduces the intracellular Aβ-induced ROS signal. In order to determine the contributions of the separate SLF moieties to these protective activities, experiments were also carried out on cells with nitroxides lacking the Aβ targeting domain or fluorene derivatives lacking the nitroxide functionality. The findings support a synergistic effect of SLF in counteracting both the conformational toxicity of both endogenous and exogenous Aβ, its promotion of ROS, and Aβ metabolism. Furthermore, these studies demonstrate an intimate link between ROS production and Aβ oligomer formation. MDPI 2018-08-12 /pmc/articles/PMC6222334/ /pubmed/30103547 http://dx.doi.org/10.3390/molecules23082010 Text en © 2018 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
Hilt, Silvia
Altman, Robin
Kálai, Tamás
Maezawa, Izumi
Gong, Qizhi
Wachsmann-Hogiu, Sebastian
Jin, Lee-Way
Voss, John C.
A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title_full A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title_fullStr A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title_full_unstemmed A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title_short A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
title_sort bifunctional anti-amyloid blocks oxidative stress and the accumulation of intraneuronal amyloid-beta
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222334/
https://www.ncbi.nlm.nih.gov/pubmed/30103547
http://dx.doi.org/10.3390/molecules23082010
work_keys_str_mv AT hiltsilvia abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT altmanrobin abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT kalaitamas abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT maezawaizumi abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT gongqizhi abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT wachsmannhogiusebastian abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT jinleeway abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT vossjohnc abifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT hiltsilvia bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT altmanrobin bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT kalaitamas bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT maezawaizumi bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT gongqizhi bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT wachsmannhogiusebastian bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT jinleeway bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta
AT vossjohnc bifunctionalantiamyloidblocksoxidativestressandtheaccumulationofintraneuronalamyloidbeta