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Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation
BACKGROUND: Alzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, ou...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709977/ https://www.ncbi.nlm.nih.gov/pubmed/29191219 http://dx.doi.org/10.1186/s13195-017-0317-z |
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author | Ochalek, Anna Mihalik, Balázs Avci, Hasan X. Chandrasekaran, Abinaya Téglási, Annamária Bock, István Giudice, Maria Lo Táncos, Zsuzsanna Molnár, Kinga László, Lajos Nielsen, Jørgen E. Holst, Bjørn Freude, Kristine Hyttel, Poul Kobolák, Julianna Dinnyés, András |
author_facet | Ochalek, Anna Mihalik, Balázs Avci, Hasan X. Chandrasekaran, Abinaya Téglási, Annamária Bock, István Giudice, Maria Lo Táncos, Zsuzsanna Molnár, Kinga László, Lajos Nielsen, Jørgen E. Holst, Bjørn Freude, Kristine Hyttel, Poul Kobolák, Julianna Dinnyés, András |
author_sort | Ochalek, Anna |
collection | PubMed |
description | BACKGROUND: Alzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. METHODS: We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer’s disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer’s disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods. RESULTS: Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-β 1–40 (Aβ(1–40)) and amyloid-β 1–42 (Aβ(1–42)). However, significantly increased Aβ(1–42)/Aβ(1–40) ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 β, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons. CONCLUSIONS: On the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aβ(1–40) levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-017-0317-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5709977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57099772017-12-06 Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation Ochalek, Anna Mihalik, Balázs Avci, Hasan X. Chandrasekaran, Abinaya Téglási, Annamária Bock, István Giudice, Maria Lo Táncos, Zsuzsanna Molnár, Kinga László, Lajos Nielsen, Jørgen E. Holst, Bjørn Freude, Kristine Hyttel, Poul Kobolák, Julianna Dinnyés, András Alzheimers Res Ther Research BACKGROUND: Alzheimer’s disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. METHODS: We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer’s disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer’s disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods. RESULTS: Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-β 1–40 (Aβ(1–40)) and amyloid-β 1–42 (Aβ(1–42)). However, significantly increased Aβ(1–42)/Aβ(1–40) ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 β, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons. CONCLUSIONS: On the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aβ(1–40) levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-017-0317-z) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-01 /pmc/articles/PMC5709977/ /pubmed/29191219 http://dx.doi.org/10.1186/s13195-017-0317-z Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ochalek, Anna Mihalik, Balázs Avci, Hasan X. Chandrasekaran, Abinaya Téglási, Annamária Bock, István Giudice, Maria Lo Táncos, Zsuzsanna Molnár, Kinga László, Lajos Nielsen, Jørgen E. Holst, Bjørn Freude, Kristine Hyttel, Poul Kobolák, Julianna Dinnyés, András Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title | Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title_full | Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title_fullStr | Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title_full_unstemmed | Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title_short | Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation |
title_sort | neurons derived from sporadic alzheimer’s disease ipscs reveal elevated tau hyperphosphorylation, increased amyloid levels, and gsk3b activation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709977/ https://www.ncbi.nlm.nih.gov/pubmed/29191219 http://dx.doi.org/10.1186/s13195-017-0317-z |
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