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Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease

BACKGROUND: Alzheimer’s disease (AD) is caused by many intertwining pathologies involving metabolic aberrations. Patients with metabolic syndrome (MetS) generally show hyperglycemia and dyslipidemia, which can lead to the formation of aldehydic adducts such as acrolein on peptides in the brain and b...

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Autores principales: Sanotra, Monika Renuka, Kao, Shu-Huei, Lee, Ching-Kuo, Hsu, Chun-Hsien, Huang, Wen-Chung, Chang, Tsuei-Chuan, Tu, Fang-Yu, Hsu, I-Uen, Lin, Yung-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286356/
https://www.ncbi.nlm.nih.gov/pubmed/37349844
http://dx.doi.org/10.1186/s13195-023-01261-2
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author Sanotra, Monika Renuka
Kao, Shu-Huei
Lee, Ching-Kuo
Hsu, Chun-Hsien
Huang, Wen-Chung
Chang, Tsuei-Chuan
Tu, Fang-Yu
Hsu, I-Uen
Lin, Yung-Feng
author_facet Sanotra, Monika Renuka
Kao, Shu-Huei
Lee, Ching-Kuo
Hsu, Chun-Hsien
Huang, Wen-Chung
Chang, Tsuei-Chuan
Tu, Fang-Yu
Hsu, I-Uen
Lin, Yung-Feng
author_sort Sanotra, Monika Renuka
collection PubMed
description BACKGROUND: Alzheimer’s disease (AD) is caused by many intertwining pathologies involving metabolic aberrations. Patients with metabolic syndrome (MetS) generally show hyperglycemia and dyslipidemia, which can lead to the formation of aldehydic adducts such as acrolein on peptides in the brain and blood. However, the pathogenesis from MetS to AD remains elusive. METHODS: An AD cell model expressing Swedish and Indiana amyloid precursor protein (APP-Swe/Ind) in neuro-2a cells and a 3xTg-AD mouse model were used. Human serum samples (142 control and 117 AD) and related clinical data were collected. Due to the involvement of MetS in AD, human samples were grouped into healthy control (HC), MetS-like, AD with normal metabolism (AD-N), and AD with metabolic disturbance (AD-M). APP, amyloid-beta (Aß), and acrolein adducts in the samples were analyzed using immunofluorescent microscopy, histochemistry, immunoprecipitation, immunoblotting, and/or ELISA. Synthetic Aß(1-16) and Aß(17-28) peptides were modified with acrolein in vitro and verified using LC–MS/MS. Native and acrolein-modified Aß peptides were used to measure the levels of specific autoantibodies IgG and IgM in the serum. The correlations and diagnostic power of potential biomarkers were evaluated. RESULTS: An increased level of acrolein adducts was detected in the AD model cells. Furthermore, acrolein adducts were observed on APP C-terminal fragments (APP-CTFs) containing Aß in 3xTg-AD mouse serum, brain lysates, and human serum. The level of acrolein adducts was correlated positively with fasting glucose and triglycerides and negatively with high-density lipoprotein-cholesterol, which correspond with MetS conditions. Among the four groups of human samples, the level of acrolein adducts was largely increased only in AD-M compared to all other groups. Notably, anti-acrolein-Aß autoantibodies, especially IgM, were largely reduced in AD-M compared to the MetS group, suggesting that the specific antibodies against acrolein adducts may be depleted during pathogenesis from MetS to AD. CONCLUSIONS: Metabolic disturbance may induce acrolein adduction, however, neutralized by responding autoantibodies. AD may be developed from MetS when these autoantibodies are depleted. Acrolein adducts and the responding autoantibodies may be potential biomarkers for not only diagnosis but also immunotherapy of AD, especially in complication with MetS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01261-2.
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spelling pubmed-102863562023-06-23 Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease Sanotra, Monika Renuka Kao, Shu-Huei Lee, Ching-Kuo Hsu, Chun-Hsien Huang, Wen-Chung Chang, Tsuei-Chuan Tu, Fang-Yu Hsu, I-Uen Lin, Yung-Feng Alzheimers Res Ther Research BACKGROUND: Alzheimer’s disease (AD) is caused by many intertwining pathologies involving metabolic aberrations. Patients with metabolic syndrome (MetS) generally show hyperglycemia and dyslipidemia, which can lead to the formation of aldehydic adducts such as acrolein on peptides in the brain and blood. However, the pathogenesis from MetS to AD remains elusive. METHODS: An AD cell model expressing Swedish and Indiana amyloid precursor protein (APP-Swe/Ind) in neuro-2a cells and a 3xTg-AD mouse model were used. Human serum samples (142 control and 117 AD) and related clinical data were collected. Due to the involvement of MetS in AD, human samples were grouped into healthy control (HC), MetS-like, AD with normal metabolism (AD-N), and AD with metabolic disturbance (AD-M). APP, amyloid-beta (Aß), and acrolein adducts in the samples were analyzed using immunofluorescent microscopy, histochemistry, immunoprecipitation, immunoblotting, and/or ELISA. Synthetic Aß(1-16) and Aß(17-28) peptides were modified with acrolein in vitro and verified using LC–MS/MS. Native and acrolein-modified Aß peptides were used to measure the levels of specific autoantibodies IgG and IgM in the serum. The correlations and diagnostic power of potential biomarkers were evaluated. RESULTS: An increased level of acrolein adducts was detected in the AD model cells. Furthermore, acrolein adducts were observed on APP C-terminal fragments (APP-CTFs) containing Aß in 3xTg-AD mouse serum, brain lysates, and human serum. The level of acrolein adducts was correlated positively with fasting glucose and triglycerides and negatively with high-density lipoprotein-cholesterol, which correspond with MetS conditions. Among the four groups of human samples, the level of acrolein adducts was largely increased only in AD-M compared to all other groups. Notably, anti-acrolein-Aß autoantibodies, especially IgM, were largely reduced in AD-M compared to the MetS group, suggesting that the specific antibodies against acrolein adducts may be depleted during pathogenesis from MetS to AD. CONCLUSIONS: Metabolic disturbance may induce acrolein adduction, however, neutralized by responding autoantibodies. AD may be developed from MetS when these autoantibodies are depleted. Acrolein adducts and the responding autoantibodies may be potential biomarkers for not only diagnosis but also immunotherapy of AD, especially in complication with MetS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01261-2. BioMed Central 2023-06-22 /pmc/articles/PMC10286356/ /pubmed/37349844 http://dx.doi.org/10.1186/s13195-023-01261-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Sanotra, Monika Renuka
Kao, Shu-Huei
Lee, Ching-Kuo
Hsu, Chun-Hsien
Huang, Wen-Chung
Chang, Tsuei-Chuan
Tu, Fang-Yu
Hsu, I-Uen
Lin, Yung-Feng
Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title_full Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title_fullStr Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title_full_unstemmed Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title_short Acrolein adducts and responding autoantibodies correlate with metabolic disturbance in Alzheimer’s disease
title_sort acrolein adducts and responding autoantibodies correlate with metabolic disturbance in alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286356/
https://www.ncbi.nlm.nih.gov/pubmed/37349844
http://dx.doi.org/10.1186/s13195-023-01261-2
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