Plasma lipoproteome in Alzheimer's disease

A proof-of-concept study

Danni Li, Fangying Huang, Yingchun Zhao, Peter W. Villata, Timothy J Griffin, Lin Zhang, Ling Li, Fang Yu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer's disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of-concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma. Methods: We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case-control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (< 0.05) or greater fold differences (> 1.05 or < 0.95) suggestive of greater peptide/protein differences. Results: Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values < 0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences > 1.05 or < 0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3's peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value < 0.05). Discussion: The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis.

Original languageEnglish (US)
Article number31
JournalClinical Proteomics
Volume15
Issue number1
DOIs
StatePublished - Sep 20 2018

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Alzheimer Disease
Plasmas
Lipoproteins
Peptides
Complement C3
Proteomics
Proteins
Social Adjustment
Ultracentrifugation
Liquid chromatography
Biomarkers
Tandem Mass Spectrometry
Serum Albumin
Liquid Chromatography
Mass spectrometry
Case-Control Studies
Immunoglobulin G
Monitoring

Keywords

  • Alzheimer's disease
  • Biomarker
  • Complement C3
  • Diagnosis
  • High-density lipoprotein (HDL)
  • Intermediate density lipoprotein (IDL)
  • Low density lipoprotein (LDL)
  • Plasma lipoproteins
  • Selected reaction monitoring (SRM)
  • Targeted proteomics
  • Very low-density lipoprotein (VLDL)

PubMed: MeSH publication types

  • Journal Article

Cite this

Plasma lipoproteome in Alzheimer's disease : A proof-of-concept study. / Li, Danni; Huang, Fangying; Zhao, Yingchun; Villata, Peter W.; Griffin, Timothy J; Zhang, Lin; Li, Ling; Yu, Fang.

In: Clinical Proteomics, Vol. 15, No. 1, 31, 20.09.2018.

Research output: Contribution to journalArticle

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keywords = "Alzheimer's disease, Biomarker, Complement C3, Diagnosis, High-density lipoprotein (HDL), Intermediate density lipoprotein (IDL), Low density lipoprotein (LDL), Plasma lipoproteins, Selected reaction monitoring (SRM), Targeted proteomics, Very low-density lipoprotein (VLDL)",
author = "Danni Li and Fangying Huang and Yingchun Zhao and Villata, {Peter W.} and Griffin, {Timothy J} and Lin Zhang and Ling Li and Fang Yu",
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language = "English (US)",
volume = "15",
journal = "Clinical Proteomics",
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T2 - A proof-of-concept study

AU - Li, Danni

AU - Huang, Fangying

AU - Zhao, Yingchun

AU - Villata, Peter W.

AU - Griffin, Timothy J

AU - Zhang, Lin

AU - Li, Ling

AU - Yu, Fang

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N2 - Background: Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer's disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of-concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma. Methods: We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case-control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (< 0.05) or greater fold differences (> 1.05 or < 0.95) suggestive of greater peptide/protein differences. Results: Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values < 0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences > 1.05 or < 0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3's peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value < 0.05). Discussion: The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis.

AB - Background: Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer's disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of-concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma. Methods: We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case-control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (< 0.05) or greater fold differences (> 1.05 or < 0.95) suggestive of greater peptide/protein differences. Results: Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values < 0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences > 1.05 or < 0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3's peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value < 0.05). Discussion: The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis.

KW - Alzheimer's disease

KW - Biomarker

KW - Complement C3

KW - Diagnosis

KW - High-density lipoprotein (HDL)

KW - Intermediate density lipoprotein (IDL)

KW - Low density lipoprotein (LDL)

KW - Plasma lipoproteins

KW - Selected reaction monitoring (SRM)

KW - Targeted proteomics

KW - Very low-density lipoprotein (VLDL)

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U2 - 10.1186/s12014-018-9207-z

DO - 10.1186/s12014-018-9207-z

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