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Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease

Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organiz...

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Autores principales: Higginbotham, Lenora, Dammer, Eric B., Duong, Duc M., Modeste, Erica, Montine, Thomas J., Lah, James J., Levey, Allan I., Seyfried, Nicholas T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789842/
https://www.ncbi.nlm.nih.gov/pubmed/31461916
http://dx.doi.org/10.3390/proteomes7030030
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author Higginbotham, Lenora
Dammer, Eric B.
Duong, Duc M.
Modeste, Erica
Montine, Thomas J.
Lah, James J.
Levey, Allan I.
Seyfried, Nicholas T.
author_facet Higginbotham, Lenora
Dammer, Eric B.
Duong, Duc M.
Modeste, Erica
Montine, Thomas J.
Lah, James J.
Levey, Allan I.
Seyfried, Nicholas T.
author_sort Higginbotham, Lenora
collection PubMed
description Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.
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spelling pubmed-67898422019-10-16 Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease Higginbotham, Lenora Dammer, Eric B. Duong, Duc M. Modeste, Erica Montine, Thomas J. Lah, James J. Levey, Allan I. Seyfried, Nicholas T. Proteomes Article Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease. MDPI 2019-08-27 /pmc/articles/PMC6789842/ /pubmed/31461916 http://dx.doi.org/10.3390/proteomes7030030 Text en © 2019 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
Higginbotham, Lenora
Dammer, Eric B.
Duong, Duc M.
Modeste, Erica
Montine, Thomas J.
Lah, James J.
Levey, Allan I.
Seyfried, Nicholas T.
Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title_full Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title_fullStr Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title_full_unstemmed Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title_short Network Analysis of a Membrane-Enriched Brain Proteome across Stages of Alzheimer’s Disease
title_sort network analysis of a membrane-enriched brain proteome across stages of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789842/
https://www.ncbi.nlm.nih.gov/pubmed/31461916
http://dx.doi.org/10.3390/proteomes7030030
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