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Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease

BACKGROUND: DYRK1A is implicated in mental retardation and Alzheimer’s disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. OBJECTIVE: Our original observations...

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Autores principales: Dowjat, Karol, Adayev, Tatyana, Wojda, Urszula, Brzozowska, Katarzyna, Barczak, Anna, Gabryelewicz, Tomasz, Hwang, Yu-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971831/
https://www.ncbi.nlm.nih.gov/pubmed/31683476
http://dx.doi.org/10.3233/JAD-190475
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author Dowjat, Karol
Adayev, Tatyana
Wojda, Urszula
Brzozowska, Katarzyna
Barczak, Anna
Gabryelewicz, Tomasz
Hwang, Yu-Wen
author_facet Dowjat, Karol
Adayev, Tatyana
Wojda, Urszula
Brzozowska, Katarzyna
Barczak, Anna
Gabryelewicz, Tomasz
Hwang, Yu-Wen
author_sort Dowjat, Karol
collection PubMed
description BACKGROUND: DYRK1A is implicated in mental retardation and Alzheimer’s disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. OBJECTIVE: Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. METHODS: Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and F-actin fractions obtained by high-speed centrifugations (spin-down assay). RESULTS: In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. CONCLUSIONS: Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD.
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spelling pubmed-69718312020-01-22 Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease Dowjat, Karol Adayev, Tatyana Wojda, Urszula Brzozowska, Katarzyna Barczak, Anna Gabryelewicz, Tomasz Hwang, Yu-Wen J Alzheimers Dis Research Article BACKGROUND: DYRK1A is implicated in mental retardation and Alzheimer’s disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. OBJECTIVE: Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. METHODS: Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and F-actin fractions obtained by high-speed centrifugations (spin-down assay). RESULTS: In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. CONCLUSIONS: Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD. IOS Press 2019-12-12 /pmc/articles/PMC6971831/ /pubmed/31683476 http://dx.doi.org/10.3233/JAD-190475 Text en © 2019 – IOS Press and the authors. All rights reserved https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Dowjat, Karol
Adayev, Tatyana
Wojda, Urszula
Brzozowska, Katarzyna
Barczak, Anna
Gabryelewicz, Tomasz
Hwang, Yu-Wen
Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title_full Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title_fullStr Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title_full_unstemmed Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title_short Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer’s Disease
title_sort abnormalities of dyrk1a-cytoskeleton complexes in the blood cells as potential biomarkers of alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971831/
https://www.ncbi.nlm.nih.gov/pubmed/31683476
http://dx.doi.org/10.3233/JAD-190475
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