Prognostic serum miRNA biomarkers associated with Alzheimer's disease shows concordance with neuropsychological and neuroimaging assessment

被引:331
作者
Cheng, L. [1 ,2 ]
Doecke, J. D. [3 ,4 ]
Sharples, R. A. [1 ,2 ]
Villemagne, V. L. [5 ,6 ,7 ]
Fowler, C. J. [8 ]
Rembach, A. [8 ]
Martins, R. N. [9 ]
Rowe, C. C. [5 ,6 ,7 ]
Macaulay, S. L. [4 ]
Masters, C. L. [8 ]
Hill, A. F. [1 ,2 ]
机构
[1] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia
[2] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic, Australia
[3] CSIRO Digital Product Flagship, Australian E Hlth Res Ctr, Herston, Qld, Australia
[4] CSIRO Food & Nutr Flagship, Melbourne, Vic, Australia
[5] Austin Hlth, Dept Nucl Med, Melbourne, Vic, Australia
[6] Austin Hlth, Ctr PET, Melbourne, Vic, Australia
[7] Austin Hlth, Dept Med, Melbourne, Vic, Australia
[8] Florey Inst, Melbourne, Vic, Australia
[9] Edith Cowan Univ, Sch Med Sci, Ctr Excellence Alzheimers Dis Res & Care, Fac Comp Hlth & Sci, Joondalup, WA, Australia
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
LIFE-STYLE; CEREBROSPINAL-FLUID; COGNITIVE DECLINE; EXOSOMES; CSF; EXPRESSION; MICRORNAS; IDENTIFICATION; SIGNATURE; DIAGNOSIS;
D O I
10.1038/mp.2014.127
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
There is no consensus for a blood-based test for the early diagnosis of Alzheimer's disease (AD). Expression profiling of small non-coding RNA's, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N = 49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N = 60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein epsilon 4 (APOE epsilon 4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.
引用
收藏
页码:1188 / 1196
页数:9
相关论文
共 47 条
[1]   Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice [J].
Andreasen, N ;
Minthon, L ;
Davidsson, P ;
Vanmechelen, E ;
Vanderstichele, H ;
Winblad, B ;
Blennow, K .
ARCHIVES OF NEUROLOGY, 2001, 58 (03) :373-379
[2]   Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10 [J].
Augustin, Regina ;
Endres, Kristina ;
Reinhardt, Sven ;
Kuhn, Peer-Hendrik ;
Lichtenthaler, Stefan F. ;
Hansen, Jens ;
Wurst, Wolfgang ;
Truembach, Dietrich .
BMC MEDICAL GENETICS, 2012, 13
[3]   Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells [J].
Bellingham, Shayne A. ;
Coleman, Bradley M. ;
Hill, Andrew F. .
NUCLEIC ACIDS RESEARCH, 2012, 40 (21) :10937-10949
[4]   Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? [J].
Bellingham, Shayne A. ;
Guo, Belinda B. ;
Coleman, Bradley M. ;
Hill, Andrew F. .
FRONTIERS IN PHYSIOLOGY, 2012, 3
[5]   Cerebrospinal fluid and plasma biomarkers in Alzheimer disease [J].
Blennow, Kaj ;
Hampel, Harald ;
Weiner, Michael ;
Zetterberg, Henrik .
NATURE REVIEWS NEUROLOGY, 2010, 6 (03) :131-144
[6]   Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood [J].
Cheng, Lesley ;
Sharples, Robyn A. ;
Scicluna, Benjamin J. ;
Hill, Andrew F. .
JOURNAL OF EXTRACELLULAR VESICLES, 2014, 3 (01)
[7]   Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine [J].
Cheng, Lesley ;
Sun, Xin ;
Scicluna, Benjamin J. ;
Coleman, Bradley M. ;
Hill, Andrew F. .
KIDNEY INTERNATIONAL, 2014, 86 (02) :433-444
[8]  
Cheng Lesley, 2013, Frontiers in Genetics, V4, P150, DOI [10.3389/fgene.2013.00150, 10.3389/fimmu.2013.00388]
[9]   Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways [J].
Cogswell, John P. ;
Ward, James ;
Taylor, Ian A. ;
Waters, Michelle ;
Shi, Yunling ;
Cannon, Brian ;
Kelnar, Kevin ;
Kemppainen, Jon ;
Brown, David ;
Chen, Caifu ;
Prinjha, Rab K. ;
Richardson, Jill C. ;
Saunders, Ann M. ;
Roses, Allen D. ;
Richards, Cynthia A. .
JOURNAL OF ALZHEIMERS DISEASE, 2008, 14 (01) :27-41
[10]   The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology [J].
Cole, Sarah L. ;
Vassar, Robert .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (44) :29621-29625