Skip to main content
Top
Published in: Alzheimer's Research & Therapy 4/2014

Open Access 01-08-2014 | Research

Differentially charged isoforms of apolipoprotein E from human blood are potential biomarkers of Alzheimer’s disease

Authors: Oscar Alzate, Cristina Osorio, Robert M DeKroon, Ana Corcimaru, Harsha P Gunawardena

Published in: Alzheimer's Research & Therapy | Issue 4/2014

Login to get access

Abstract

Introduction

Alzheimer’s disease (AD) is the major cause of dementia among the elderly. Finding blood-based biomarkers for disease diagnosis and prognosis is urgently needed.

Methods

We studied protein distributions in brain tissues, cerebrospinal fluid (CSF), and blood of AD patients by using proteomics and a new proteomic method that we call “2D multiplexed Western blot” (2D mxWd). This method allows us to determine in multiple samples the electrophoretic patterns of protein isoforms with different isoelectric points.

Results

Apolipoprotein E (ApoE) displays a unique distribution of electrophoretic isoforms in the presence of AD and also a unique pattern specific to the APOE genotype.

Conclusions

The isoelectric distribution of differentially charged ApoE isoforms was used to determine the presence of AD in a small group of samples. Further studies are needed to validate their use as predictors of disease onset and progression, and as biomarkers for determining the efficacy of therapeutic treatments.
Appendix
Available only for authorised users
Literature
1.
go back to reference Thies W, Bleiler L: Alzheimer’s disease facts and figures. Alzheimers Dement. 2011, 2011: 208-244. Thies W, Bleiler L: Alzheimer’s disease facts and figures. Alzheimers Dement. 2011, 2011: 208-244.
2.
go back to reference Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer’s disease genetic association studies: the AlzGene database. Nat Genet. 2007, 39: 17-23. 10.1038/ng1934.CrossRefPubMed Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer’s disease genetic association studies: the AlzGene database. Nat Genet. 2007, 39: 17-23. 10.1038/ng1934.CrossRefPubMed
3.
go back to reference Roses AD: Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996, 47: 387-400. 10.1146/annurev.med.47.1.387.CrossRefPubMed Roses AD: Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996, 47: 387-400. 10.1146/annurev.med.47.1.387.CrossRefPubMed
4.
go back to reference Roses AD: Apolipoprotein E, a gene with complex biological interactions in the aging brain. Neurobiol Dis. 1997, 4: 170-185. 10.1006/nbdi.1997.0161.CrossRefPubMed Roses AD: Apolipoprotein E, a gene with complex biological interactions in the aging brain. Neurobiol Dis. 1997, 4: 170-185. 10.1006/nbdi.1997.0161.CrossRefPubMed
5.
go back to reference Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci U S A. 1993, 90: 1977-1981. 10.1073/pnas.90.5.1977.PubMedCentralCrossRefPubMed Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci U S A. 1993, 90: 1977-1981. 10.1073/pnas.90.5.1977.PubMedCentralCrossRefPubMed
6.
go back to reference Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD: Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A. 1993, 90: 8098-8102. 10.1073/pnas.90.17.8098.PubMedCentralCrossRefPubMed Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD: Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A. 1993, 90: 8098-8102. 10.1073/pnas.90.17.8098.PubMedCentralCrossRefPubMed
7.
go back to reference Thambisetty M, An Y, Tanaka T: Alzheimer’s disease risk genes and the age-at-onset phenotype. Neurobiol Aging. 2013, 34: 2696. e1-5-CrossRefPubMed Thambisetty M, An Y, Tanaka T: Alzheimer’s disease risk genes and the age-at-onset phenotype. Neurobiol Aging. 2013, 34: 2696. e1-5-CrossRefPubMed
8.
go back to reference Mahley RW: Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988, 240: 622-630. 10.1126/science.3283935.CrossRefPubMed Mahley RW: Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988, 240: 622-630. 10.1126/science.3283935.CrossRefPubMed
9.
go back to reference Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006, 103: 5644-5651. 10.1073/pnas.0600549103.PubMedCentralCrossRefPubMed Mahley RW, Weisgraber KH, Huang Y: Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006, 103: 5644-5651. 10.1073/pnas.0600549103.PubMedCentralCrossRefPubMed
10.
go back to reference Blennow K, Vanmechelen E, Hampel H: CSF Total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol. 2001, 24: 87-97. 10.1385/MN:24:1-3:087.CrossRefPubMed Blennow K, Vanmechelen E, Hampel H: CSF Total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol. 2001, 24: 87-97. 10.1385/MN:24:1-3:087.CrossRefPubMed
11.
go back to reference Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, Hochstrasser DF, Sanchez JC: A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease. Proteomics. 2003, 3: 1486-1494. 10.1002/pmic.200300470.CrossRefPubMed Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, Hochstrasser DF, Sanchez JC: A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease. Proteomics. 2003, 3: 1486-1494. 10.1002/pmic.200300470.CrossRefPubMed
12.
go back to reference Finehout EJ, Franck Z, Choe LH, Relkin N, Lee KH: Cerebrospinal fluid proteomic biomarkers for Alzheimer’s disease. Ann Neurol. 2007, 61: 120-129. 10.1002/ana.21038.CrossRefPubMed Finehout EJ, Franck Z, Choe LH, Relkin N, Lee KH: Cerebrospinal fluid proteomic biomarkers for Alzheimer’s disease. Ann Neurol. 2007, 61: 120-129. 10.1002/ana.21038.CrossRefPubMed
13.
go back to reference Raedler TJ, Wiedemann K: CSF studies in neuropsychiatric disorders. Neuro Endocrinol Lett. 2006, 27: 297-305.PubMed Raedler TJ, Wiedemann K: CSF studies in neuropsychiatric disorders. Neuro Endocrinol Lett. 2006, 27: 297-305.PubMed
14.
go back to reference Zhang J, Goodlett DR, Peskind ER, Quinn JF, Zhou Y, Wang Q, Pan C, Yi E, Eng J, Aebersold RH, Montine TJ: Quantitative proteomic analysis of age-related changes in human cerebrospinal fluid. Neurobiol Aging. 2005, 26: 207-227. 10.1016/j.neurobiolaging.2004.03.012.CrossRefPubMed Zhang J, Goodlett DR, Peskind ER, Quinn JF, Zhou Y, Wang Q, Pan C, Yi E, Eng J, Aebersold RH, Montine TJ: Quantitative proteomic analysis of age-related changes in human cerebrospinal fluid. Neurobiol Aging. 2005, 26: 207-227. 10.1016/j.neurobiolaging.2004.03.012.CrossRefPubMed
15.
go back to reference Zhang J, Goodlett DR, Quinn JF, Peskind E, Kaye JA, Zhou Y, Pan C, Yi E, Eng J, Wang Q, Aebersold RH, Montine TJ: Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer’s disease. J Alzheimers Dis. 2005, 7: 125-133. discussion 173–180PubMed Zhang J, Goodlett DR, Quinn JF, Peskind E, Kaye JA, Zhou Y, Pan C, Yi E, Eng J, Wang Q, Aebersold RH, Montine TJ: Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer’s disease. J Alzheimers Dis. 2005, 7: 125-133. discussion 173–180PubMed
16.
go back to reference Zhang J, Montine TJ: Proteomic discovery of CSF biomarkers for Alzheimer’s disease. Ann Neurol. 2007, 61: 497-author reply 497–498CrossRefPubMed Zhang J, Montine TJ: Proteomic discovery of CSF biomarkers for Alzheimer’s disease. Ann Neurol. 2007, 61: 497-author reply 497–498CrossRefPubMed
17.
go back to reference Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T: Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol. 2009, 66: 382-389.CrossRefPubMed Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T: Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol. 2009, 66: 382-389.CrossRefPubMed
18.
go back to reference Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL, Martins RN: Blood-based protein biomarkers for diagnosis of Alzheimer’s disease. Arch Neurol. 2012, 69: 1318-1325. 10.1001/archneurol.2012.1282.CrossRefPubMed Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL, Martins RN: Blood-based protein biomarkers for diagnosis of Alzheimer’s disease. Arch Neurol. 2012, 69: 1318-1325. 10.1001/archneurol.2012.1282.CrossRefPubMed
19.
go back to reference Osorio C, Sullivan PM, He DN, Mace BE, Ervin JF, Strittmatter WJ, Alzate O: Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice. Neurobiol Aging. 2007, 28: 1853-1862. 10.1016/j.neurobiolaging.2006.08.011.CrossRefPubMed Osorio C, Sullivan PM, He DN, Mace BE, Ervin JF, Strittmatter WJ, Alzate O: Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice. Neurobiol Aging. 2007, 28: 1853-1862. 10.1016/j.neurobiolaging.2006.08.011.CrossRefPubMed
20.
go back to reference Ervin JF: Banking tissue for neurodegenerative research. Neuroproteomics. Edited by: Alzate O. 2010, Boca Raton, (FL): Frontiers in Neuroscience Ervin JF: Banking tissue for neurodegenerative research. Neuroproteomics. Edited by: Alzate O. 2010, Boca Raton, (FL): Frontiers in Neuroscience
21.
go back to reference DeKroon RM, Osorio C, Robinette JB, Mocanu M, Winnik WM, Alzate O: Simultaneous detection of changes in protein expression and oxidative modification as a function of age and APOE genotype. J Proteome Res. 2011, 10: 1632-1644. 10.1021/pr1009788.CrossRefPubMed DeKroon RM, Osorio C, Robinette JB, Mocanu M, Winnik WM, Alzate O: Simultaneous detection of changes in protein expression and oxidative modification as a function of age and APOE genotype. J Proteome Res. 2011, 10: 1632-1644. 10.1021/pr1009788.CrossRefPubMed
22.
go back to reference Botero LE, Toro AE, Patino AJ, Salazar G, Rodriguez JC, Suarez-Escudero JC, Alarcon GA, Corcimaru A, Osorio C, Jeong JS, Alzate O: Diabetes mellitus in patients with Alzheimer’s disease: clinical description and correlation with the APOE genotype in a sample population from the province of Antioquia, Colombia. Biomedica. 2012, 32: 239-251.CrossRefPubMed Botero LE, Toro AE, Patino AJ, Salazar G, Rodriguez JC, Suarez-Escudero JC, Alarcon GA, Corcimaru A, Osorio C, Jeong JS, Alzate O: Diabetes mellitus in patients with Alzheimer’s disease: clinical description and correlation with the APOE genotype in a sample population from the province of Antioquia, Colombia. Biomedica. 2012, 32: 239-251.CrossRefPubMed
23.
go back to reference Wessel D, Flugge UI: A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 1984, 138: 141-143. 10.1016/0003-2697(84)90782-6.CrossRefPubMed Wessel D, Flugge UI: A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 1984, 138: 141-143. 10.1016/0003-2697(84)90782-6.CrossRefPubMed
24.
go back to reference Friedman DB, Lilley KS: Optimizing the difference gel electrophoresis (DIGE) technology. Methods Mol Biol. 2008, 428: 93-124. 10.1007/978-1-59745-117-8_6.CrossRefPubMed Friedman DB, Lilley KS: Optimizing the difference gel electrophoresis (DIGE) technology. Methods Mol Biol. 2008, 428: 93-124. 10.1007/978-1-59745-117-8_6.CrossRefPubMed
25.
go back to reference Friedman DB: Assessing signal-to-noise in quantitative proteomics: multivariate statistical analysis in DIGE experiments. Methods Mol Biol. 2012, 854: 31-45. 10.1007/978-1-61779-573-2_4.CrossRefPubMed Friedman DB: Assessing signal-to-noise in quantitative proteomics: multivariate statistical analysis in DIGE experiments. Methods Mol Biol. 2012, 854: 31-45. 10.1007/978-1-61779-573-2_4.CrossRefPubMed
26.
go back to reference Winnik WM, Dekroon RM, Jeong JS, Mocanu M, Robinette JB, Osorio C, Dicheva NN, Hamlett E, Alzate O: Analysis of proteins using DIGE and MALDI mass spectrometry. Methods Mol Biol. 2012, 854: 47-66. 10.1007/978-1-61779-573-2_5.CrossRefPubMed Winnik WM, Dekroon RM, Jeong JS, Mocanu M, Robinette JB, Osorio C, Dicheva NN, Hamlett E, Alzate O: Analysis of proteins using DIGE and MALDI mass spectrometry. Methods Mol Biol. 2012, 854: 47-66. 10.1007/978-1-61779-573-2_5.CrossRefPubMed
27.
go back to reference Pinaud R, Osorio C, Alzate O, Jarvis ED: Profiling of experience-regulated proteins in the songbird auditory forebrain using quantitative proteomics. Eur J Neurosci. 2008, 27: 1409-1422. 10.1111/j.1460-9568.2008.06102.x.PubMedCentralCrossRefPubMed Pinaud R, Osorio C, Alzate O, Jarvis ED: Profiling of experience-regulated proteins in the songbird auditory forebrain using quantitative proteomics. Eur J Neurosci. 2008, 27: 1409-1422. 10.1111/j.1460-9568.2008.06102.x.PubMedCentralCrossRefPubMed
29.
go back to reference Graves DJ, Martin BL, Wang JH: Co- and Post-Translational Modifications of Proteins: Chemical Principles and Biological Effects. 1994, New York: Oxford University Press Graves DJ, Martin BL, Wang JH: Co- and Post-Translational Modifications of Proteins: Chemical Principles and Biological Effects. 1994, New York: Oxford University Press
30.
go back to reference Walsh CT, Garneau-Tsodikova S, Gatto GJ: Protein posttranslational modifications: the chemistry of proteome diversifications. Agnew Chem Int Ed Engl. 2005, 44: 7342-7372. 10.1002/anie.200501023.CrossRef Walsh CT, Garneau-Tsodikova S, Gatto GJ: Protein posttranslational modifications: the chemistry of proteome diversifications. Agnew Chem Int Ed Engl. 2005, 44: 7342-7372. 10.1002/anie.200501023.CrossRef
31.
go back to reference Dekroon RM, Robinette JB, Osorio C, Jeong JS, Hamlett E, Mocanu M, Alzate O: Analysis of protein posttranslational modifications using DIGE-based proteomics. Methods Mol Biol. 2012, 854: 129-143. 10.1007/978-1-61779-573-2_9.CrossRefPubMed Dekroon RM, Robinette JB, Osorio C, Jeong JS, Hamlett E, Mocanu M, Alzate O: Analysis of protein posttranslational modifications using DIGE-based proteomics. Methods Mol Biol. 2012, 854: 129-143. 10.1007/978-1-61779-573-2_9.CrossRefPubMed
33.
go back to reference Elias JE, Gygi SP: Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods. 2007, 4: 207-214. 10.1038/nmeth1019.CrossRefPubMed Elias JE, Gygi SP: Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods. 2007, 4: 207-214. 10.1038/nmeth1019.CrossRefPubMed
34.
go back to reference Hsieh EJ, Hoopmann MR, MacLean B, MacCoss MJ: Comparison of database search strategies for high precursor mass accuracy MS/MS data. J Proteome Res. 2010, 9: 1138-1143. 10.1021/pr900816a.PubMedCentralCrossRefPubMed Hsieh EJ, Hoopmann MR, MacLean B, MacCoss MJ: Comparison of database search strategies for high precursor mass accuracy MS/MS data. J Proteome Res. 2010, 9: 1138-1143. 10.1021/pr900816a.PubMedCentralCrossRefPubMed
35.
go back to reference Nesvizhskii AI, Keller A, Kolker E, Aebersold R: A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem. 2003, 75: 4646-4658. 10.1021/ac0341261.CrossRefPubMed Nesvizhskii AI, Keller A, Kolker E, Aebersold R: A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem. 2003, 75: 4646-4658. 10.1021/ac0341261.CrossRefPubMed
36.
go back to reference Keller A, Nesvizhskii AI, Kolker E, Aebersold R: Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal Chem. 2002, 74: 5383-5392. 10.1021/ac025747h.CrossRefPubMed Keller A, Nesvizhskii AI, Kolker E, Aebersold R: Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal Chem. 2002, 74: 5383-5392. 10.1021/ac025747h.CrossRefPubMed
39.
go back to reference Cooper B, Feng J, Garrett WM: Relative, label-free protein quantitation: spectral counting error statistics from nine replicate MudPIT samples. J Am Soc Mass Spectrom. 2010, 21: 1534-1546. 10.1016/j.jasms.2010.05.001.CrossRefPubMed Cooper B, Feng J, Garrett WM: Relative, label-free protein quantitation: spectral counting error statistics from nine replicate MudPIT samples. J Am Soc Mass Spectrom. 2010, 21: 1534-1546. 10.1016/j.jasms.2010.05.001.CrossRefPubMed
40.
go back to reference Zhu W, Smith JW, Huang CM: Mass spectrometry-based label-free quantitative proteomics. J Biomed Biotechnol. 2010, 2010: 840518-PubMedCentralPubMed Zhu W, Smith JW, Huang CM: Mass spectrometry-based label-free quantitative proteomics. J Biomed Biotechnol. 2010, 2010: 840518-PubMedCentralPubMed
Metadata
Title
Differentially charged isoforms of apolipoprotein E from human blood are potential biomarkers of Alzheimer’s disease
Authors
Oscar Alzate
Cristina Osorio
Robert M DeKroon
Ana Corcimaru
Harsha P Gunawardena
Publication date
01-08-2014
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 4/2014
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/alzrt273

Other articles of this Issue 4/2014

Alzheimer's Research & Therapy 4/2014 Go to the issue