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Published in: Alzheimer's Research & Therapy 1/2017

Open Access 01-12-2017 | Research

Dynamic changes of oligomeric amyloid β levels in plasma induced by spiked synthetic Aβ42

Authors: Seong Soo A. An, Byoung-sub Lee, Ji Sun Yu, Kuntaek Lim, Gwang Je Kim, Ryan Lee, Shinwon Kim, Sungmin Kang, Young Ho Park, Min Jeong Wang, Young Soon Yang, Young Chul Youn, SangYun Kim

Published in: Alzheimer's Research & Therapy | Issue 1/2017

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Abstract

Background

A reliable blood-based assay is required to properly diagnose and monitor Alzheimer’s disease (AD). Many attempts have been made to develop such a diagnostic tool by measuring amyloid-β oligomers (AβOs) in the blood, but none have been successful in terms of method reliability. We present a multimer detection system (MDS), initially developed for the detection of prion oligomers in the blood, to detect AβOs.

Methods

To characterize Aβ in the blood, plasma was spiked with synthetic amyloid-β (Aβ) and incubated over time. Then, the MDS was used to monitor the dynamic changes of AβO levels in the plasma.

Results

Increasing concentrations of AβOs were observed in the plasma of patients with AD but not in the plasma of normal control subjects. The plasma from patients with AD (n = 27) was differentiated from that of the age-matched normal control subjects (n = 144) with a sensitivity of 83.3% and a specificity of 90.0%.

Conclusions

Synthetic Aβ spiked into the blood plasma of patients with AD, but that of not elderly normal control subjects, induced dynamic changes in the formation of AβOs over time. AβOs were detected by the MDS, which is a useful blood-based assay with high sensitivity and specificity for AD diagnosis.
Literature
1.
go back to reference Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.CrossRefPubMed Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.CrossRefPubMed
3.
go back to reference Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.CrossRefPubMed Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.CrossRefPubMed
4.
go back to reference Jan A, Adolfsson O, Allaman I, Buccarello AL, Magistretti PJ, Pfeifer A, et al. Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. J Biol Chem. 2011;286(10):8585–96.CrossRefPubMed Jan A, Adolfsson O, Allaman I, Buccarello AL, Magistretti PJ, Pfeifer A, et al. Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. J Biol Chem. 2011;286(10):8585–96.CrossRefPubMed
5.
go back to reference Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101–12.CrossRefPubMed Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101–12.CrossRefPubMed
6.
go back to reference Kittelberger KA, Piazza F, Tesco G, Reijmers LG. Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice. PLoS One. 2012;7(1), e29940.CrossRefPubMedPubMedCentral Kittelberger KA, Piazza F, Tesco G, Reijmers LG. Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice. PLoS One. 2012;7(1), e29940.CrossRefPubMedPubMedCentral
7.
go back to reference Poling A, Morgan-Paisley K, Panos JJ, Kim EM, O’Hare E, Cleary JP, et al. Oligomers of the amyloid-β protein disrupt working memory: confirmation with two behavioral procedures. Behav Brain Res. 2008;193(2):230–4.CrossRefPubMedPubMedCentral Poling A, Morgan-Paisley K, Panos JJ, Kim EM, O’Hare E, Cleary JP, et al. Oligomers of the amyloid-β protein disrupt working memory: confirmation with two behavioral procedures. Behav Brain Res. 2008;193(2):230–4.CrossRefPubMedPubMedCentral
8.
go back to reference Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci. 2005;8(1):79–84.CrossRefPubMed Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci. 2005;8(1):79–84.CrossRefPubMed
9.
go back to reference Ferreira ST, Vieira MN, De Felice FG. Soluble protein oligomers as emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life. 2007;59(4-5):332–45.CrossRefPubMed Ferreira ST, Vieira MN, De Felice FG. Soluble protein oligomers as emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life. 2007;59(4-5):332–45.CrossRefPubMed
10.
go back to reference Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15(3):349–57.CrossRefPubMed Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15(3):349–57.CrossRefPubMed
12.
go back to reference Choi YJ, Chae S, Kim JH, Barald KF, Park JY, Lee SH. Neurotoxic amyloid β oligomeric assemblies recreated in microfluidic platform with interstitial level of slow flow. Sci Rep. 2013;3:1921.CrossRefPubMedPubMedCentral Choi YJ, Chae S, Kim JH, Barald KF, Park JY, Lee SH. Neurotoxic amyloid β oligomeric assemblies recreated in microfluidic platform with interstitial level of slow flow. Sci Rep. 2013;3:1921.CrossRefPubMedPubMedCentral
13.
go back to reference Cedazo-Minguez A, Winblad B. Biomarkers for Alzheimer’s disease and other forms of dementia: clinical needs, limitations and future aspects. Exp Gerontol. 2010;45(1):5–14.CrossRefPubMed Cedazo-Minguez A, Winblad B. Biomarkers for Alzheimer’s disease and other forms of dementia: clinical needs, limitations and future aspects. Exp Gerontol. 2010;45(1):5–14.CrossRefPubMed
14.
go back to reference Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–44.CrossRefPubMed Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6(3):131–44.CrossRefPubMed
15.
go back to reference Yang L, Rieves D, Ganley C. Brain amyloid imaging—FDA approval of florbetapir F18 injection. N Engl J Med. 2012;367(10):885–7.CrossRefPubMed Yang L, Rieves D, Ganley C. Brain amyloid imaging—FDA approval of florbetapir F18 injection. N Engl J Med. 2012;367(10):885–7.CrossRefPubMed
16.
go back to reference Ewers M, Sperling RA, Klunk WE, Weiner MW, Hampel H. Neuroimaging markers for the prediction and early diagnosis of Alzheimer’s disease dementia. Trends Neurosci. 2011;34(8):430–42.CrossRefPubMedPubMedCentral Ewers M, Sperling RA, Klunk WE, Weiner MW, Hampel H. Neuroimaging markers for the prediction and early diagnosis of Alzheimer’s disease dementia. Trends Neurosci. 2011;34(8):430–42.CrossRefPubMedPubMedCentral
17.
go back to reference Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in Alzheimer disease. Nat Rev Neurol. 2010;6(2):78–87.CrossRefPubMed Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in Alzheimer disease. Nat Rev Neurol. 2010;6(2):78–87.CrossRefPubMed
18.
go back to reference Wang C, Cui Y, Yang J, Zhang J, Yuan D, Wei Y, et al. Combining serum and urine biomarkers in the early diagnosis of mild cognitive impairment that evolves into Alzheimer’s disease in patients with the apolipoprotein E4 genotype. Biomarkers. 2015;20(1):84–8.CrossRefPubMed Wang C, Cui Y, Yang J, Zhang J, Yuan D, Wei Y, et al. Combining serum and urine biomarkers in the early diagnosis of mild cognitive impairment that evolves into Alzheimer’s disease in patients with the apolipoprotein E4 genotype. Biomarkers. 2015;20(1):84–8.CrossRefPubMed
19.
go back to reference Ma L, Chen J, Wang R, Han Y, Zhang J, Dong W, et al. The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment. J Clin Neurosci. 2015;22(4):649–52.CrossRefPubMed Ma L, Chen J, Wang R, Han Y, Zhang J, Dong W, et al. The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment. J Clin Neurosci. 2015;22(4):649–52.CrossRefPubMed
20.
go back to reference Ma L, Wang R, Han Y, Sheng S, Zhu J, Ji Z, et al. Development of a novel urine Alzheimer-associated neuronal thread protein ELISA kit and its potential use in the diagnosis of Alzheimer’s disease. J Clin Lab Anal. 2015;30(4):308–14.CrossRefPubMed Ma L, Wang R, Han Y, Sheng S, Zhu J, Ji Z, et al. Development of a novel urine Alzheimer-associated neuronal thread protein ELISA kit and its potential use in the diagnosis of Alzheimer’s disease. J Clin Lab Anal. 2015;30(4):308–14.CrossRefPubMed
21.
go back to reference Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol. 2010;10:108.CrossRefPubMedPubMedCentral Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol. 2010;10:108.CrossRefPubMedPubMedCentral
22.
go back to reference Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014;20(4):415–8.CrossRefPubMedPubMedCentral Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014;20(4):415–8.CrossRefPubMedPubMedCentral
23.
go back to reference Ait-ghezala G, Abdullah L, Volmar CH, Paris D, Luis CA, Quadros A, et al. Diagnostic utility of APOE, soluble CD40, CD40L, and Aβ1–40 levels in plasma in Alzheimer’s disease. Cytokine. 2008;44(2):283–7.CrossRefPubMed Ait-ghezala G, Abdullah L, Volmar CH, Paris D, Luis CA, Quadros A, et al. Diagnostic utility of APOE, soluble CD40, CD40L, and Aβ1–40 levels in plasma in Alzheimer’s disease. Cytokine. 2008;44(2):283–7.CrossRefPubMed
24.
go back to reference Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, et al. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol. 2012;69(10):1318–25.CrossRefPubMed Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, et al. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol. 2012;69(10):1318–25.CrossRefPubMed
25.
go back to reference Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359–62.CrossRefPubMed Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359–62.CrossRefPubMed
26.
go back to reference Xia W, Yang T, Shankar G, Smith IM, Shen Y, Walsh DM, Selkoe DJ. A specific enzyme-linked immunosorbent assay for measuring β-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol. 2009;66(2):190–9.CrossRefPubMedPubMedCentral Xia W, Yang T, Shankar G, Smith IM, Shen Y, Walsh DM, Selkoe DJ. A specific enzyme-linked immunosorbent assay for measuring β-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol. 2009;66(2):190–9.CrossRefPubMedPubMedCentral
27.
go back to reference Bjorkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS One. 2012;7(1), e29868.CrossRefPubMedPubMedCentral Bjorkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS One. 2012;7(1), e29868.CrossRefPubMedPubMedCentral
28.
go back to reference Yang T, Hong S, O’Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF. Alzheimers Dement. 2013;9(2):99–112.CrossRefPubMedPubMedCentral Yang T, Hong S, O’Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF. Alzheimers Dement. 2013;9(2):99–112.CrossRefPubMedPubMedCentral
29.
go back to reference Hyman BT, Smith C, Buldyrev I, Whelan C, Brown H, Tang MX, Mayeux R. Autoantibodies to amyloid-β and Alzheimer’s disease. Ann Neurol. 2001;49(6):808–10.CrossRefPubMed Hyman BT, Smith C, Buldyrev I, Whelan C, Brown H, Tang MX, Mayeux R. Autoantibodies to amyloid-β and Alzheimer’s disease. Ann Neurol. 2001;49(6):808–10.CrossRefPubMed
32.
go back to reference Hampel H, Shen Y, Walsh DM, Aisen P, Shaw LM, Zetterberg H, et al. Biological markers of amyloid β-related mechanisms in Alzheimer’s disease. Exp Neurol. 2010;223(2):334–46.CrossRefPubMed Hampel H, Shen Y, Walsh DM, Aisen P, Shaw LM, Zetterberg H, et al. Biological markers of amyloid β-related mechanisms in Alzheimer’s disease. Exp Neurol. 2010;223(2):334–46.CrossRefPubMed
33.
go back to reference An SSA, Lim KT, Oh HJ, Lee BS, Zukic E, Ju YR, et al. Differentiating blood samples from scrapie infected and non-infected hamsters by detecting disease-associated prion proteins using multimer detection system. Biochem Biophys Res Commun. 2010;392(4):505–9.CrossRefPubMed An SSA, Lim KT, Oh HJ, Lee BS, Zukic E, Ju YR, et al. Differentiating blood samples from scrapie infected and non-infected hamsters by detecting disease-associated prion proteins using multimer detection system. Biochem Biophys Res Commun. 2010;392(4):505–9.CrossRefPubMed
35.
go back to reference Wang YJ, Zhou HD, Zhou XF. Clearance of amyloid-β in Alzheimer’s disease: progress, problems and perspectives. Drug Discov Today. 2006;11(19-20):931–8.CrossRefPubMed Wang YJ, Zhou HD, Zhou XF. Clearance of amyloid-β in Alzheimer’s disease: progress, problems and perspectives. Drug Discov Today. 2006;11(19-20):931–8.CrossRefPubMed
36.
go back to reference Sehlin D, Söllvander S, Paulie S, Brundin R, Ingelsson M, Lannfelt L, et al. Interference from heterophilic antibodies in amyloid-β oligomer ELISAs. J Alzheimers Dis. 2010;21(4):1295–301.CrossRefPubMed Sehlin D, Söllvander S, Paulie S, Brundin R, Ingelsson M, Lannfelt L, et al. Interference from heterophilic antibodies in amyloid-β oligomer ELISAs. J Alzheimers Dis. 2010;21(4):1295–301.CrossRefPubMed
37.
go back to reference Kuo YM, Emmerling MR, Lampert HC, Hempelman SR, Kokjohn TA, Woods AS, et al. High levels of circulating Aβ42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun. 1999;257(3):787–91.CrossRefPubMed Kuo YM, Emmerling MR, Lampert HC, Hempelman SR, Kokjohn TA, Woods AS, et al. High levels of circulating Aβ42 are sequestered by plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun. 1999;257(3):787–91.CrossRefPubMed
38.
go back to reference Kuo YM, Kokjohn TA, Kalback W, Luehrs D, Galasko DR, Chevallier N, et al. Amyloid-β peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem Biophys Res Commun. 2000;268(3):750–6.CrossRefPubMed Kuo YM, Kokjohn TA, Kalback W, Luehrs D, Galasko DR, Chevallier N, et al. Amyloid-β peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem Biophys Res Commun. 2000;268(3):750–6.CrossRefPubMed
39.
go back to reference Lim K, Kim SY, Lee B, Segarra C, Kang S, Ju Y, et al. Magnetic microparticle-based multimer detection system for the detection of prion oligomers in sheep. Int J Nanomed. 2015;10(Spec Iss):241–50. Lim K, Kim SY, Lee B, Segarra C, Kang S, Ju Y, et al. Magnetic microparticle-based multimer detection system for the detection of prion oligomers in sheep. Int J Nanomed. 2015;10(Spec Iss):241–50.
40.
go back to reference Ono K, Noguchi-Shinohara M, Samuraki M, Matsumoto Y, Yanase D, et al. Blood-borne factors inhibit Alzheimer’s β-amyloid fibril formation in vitro. Exp Neurol. 2006;202(1):125–32.CrossRefPubMed Ono K, Noguchi-Shinohara M, Samuraki M, Matsumoto Y, Yanase D, et al. Blood-borne factors inhibit Alzheimer’s β-amyloid fibril formation in vitro. Exp Neurol. 2006;202(1):125–32.CrossRefPubMed
41.
go back to reference Jarrett JT, Lansbury Jr PT. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell. 1993;73(6):1055–8.CrossRefPubMed Jarrett JT, Lansbury Jr PT. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell. 1993;73(6):1055–8.CrossRefPubMed
42.
go back to reference Ghosh P, Kumar A, Datta B, Rangachari V. Dynamics of protofibril elongation and association involved in Aβ42 peptide aggregation in Alzheimer’s disease. BMC Bioinform. 2010;11 Suppl 6:S24.CrossRef Ghosh P, Kumar A, Datta B, Rangachari V. Dynamics of protofibril elongation and association involved in Aβ42 peptide aggregation in Alzheimer’s disease. BMC Bioinform. 2010;11 Suppl 6:S24.CrossRef
43.
go back to reference Jeong JS, Ansaloni A, Mezzenga R, Lashuel HA, Dietler G. Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation. J Mol Biol. 2013;425(10):1765–81.CrossRefPubMed Jeong JS, Ansaloni A, Mezzenga R, Lashuel HA, Dietler G. Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation. J Mol Biol. 2013;425(10):1765–81.CrossRefPubMed
44.
go back to reference Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C. Detection of misfolded Aβ oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Rep. 2014;7(1):261–8.CrossRefPubMed Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C. Detection of misfolded Aβ oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Rep. 2014;7(1):261–8.CrossRefPubMed
45.
go back to reference Roher AE, Esh CL, Kokjohn TA, Castaño EM, Van Vickle GD, Kalback WM, et al. Amyloid β peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement. 2009;5(1):18–29.CrossRefPubMedPubMedCentral Roher AE, Esh CL, Kokjohn TA, Castaño EM, Van Vickle GD, Kalback WM, et al. Amyloid β peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimers Dement. 2009;5(1):18–29.CrossRefPubMedPubMedCentral
46.
go back to reference Arai H, Lee VM, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ. Expression patterns of β-amyloid precursor protein (β-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann Neurol. 1991;30(5):686–93.CrossRefPubMed Arai H, Lee VM, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ. Expression patterns of β-amyloid precursor protein (β-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann Neurol. 1991;30(5):686–93.CrossRefPubMed
47.
go back to reference Clifford PM, Zarrabi S, Siu G, Kinsler KJ, Kosciuk MC, Venkataraman V, et al. Aβ peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons. Brain Res. 2007;1142:223–36.CrossRefPubMed Clifford PM, Zarrabi S, Siu G, Kinsler KJ, Kosciuk MC, Venkataraman V, et al. Aβ peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons. Brain Res. 2007;1142:223–36.CrossRefPubMed
48.
go back to reference Cho SM, Kim HV, Lee S, Kim HY, Kim W, Kim TS, et al. Correlations of amyloid-β concentrations between CSF and plasma in acute Alzheimer mouse model. Sci Rep. 2014;4:6777.CrossRefPubMedPubMedCentral Cho SM, Kim HV, Lee S, Kim HY, Kim W, Kim TS, et al. Correlations of amyloid-β concentrations between CSF and plasma in acute Alzheimer mouse model. Sci Rep. 2014;4:6777.CrossRefPubMedPubMedCentral
Metadata
Title
Dynamic changes of oligomeric amyloid β levels in plasma induced by spiked synthetic Aβ42
Authors
Seong Soo A. An
Byoung-sub Lee
Ji Sun Yu
Kuntaek Lim
Gwang Je Kim
Ryan Lee
Shinwon Kim
Sungmin Kang
Young Ho Park
Min Jeong Wang
Young Soon Yang
Young Chul Youn
SangYun Kim
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2017
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-017-0310-6

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