Abstract
Background
Diagnosis of current Alzheimer’s disease (AD) is difficult even for medical specialists, and there is no clear biomarker. Also, aging is highly related to the onset of AD.
Objectives
The purpose of this study is to screen miRNA as an aging-considered biomarker for AD treatment and diagnosis.
Methods
The patient group for this study was divided into a young normal, old normal, or AD group. We developed a method of discovering sequentially expressed miRNAs to distinguish miRNAs that were sequentially expressed in the three groups.
Results
Sequentially expressed miRNAs correlated highly with the patient’s age, and most showed expression patterns that distinguished young, old, and AD. Specifically, the miRNA expression we found showed similar patterns in the brains of patients with AD. Among the selected miRNAs, one set derived from the same precursor: The expression of miR-150 was a disease- and age-specific downregulation in both 3p and 5p forms, and the precursor also had the same pattern. We named that triple matching. Also, the found miR-150 precursor had AD-specific miRNA-imbalance characteristics.
Conclusions
We developed a novel AD diagnostic method using triple matching and miRNA-imbalance. The triple matching and miRNA imbalance-based relative ratio diagnosis method we developed will be very powerful in resolving the challenges of absolute diagnostic quantification based on biomarker expression. Also, our research results suggest the possibility of a treatment target for AD.
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References
Bartzokis G (2011) Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging 32:1341–1371
Bissels U, Wild S, Tomiuk S, Holste A, Hafner M, Tuschl T, Bosio A (2009) Absolute quantification of microRNAs by using a universal reference. RNA 15:2375–2384
Boese AS, Saba R, Campbell K, Majer A, Medina S, Burton L, Booth TF, Chong P, Westmacott G, Dutta SM (2016) MicroRNA abundance is altered in synaptoneurosomes during prion disease . Mol Cell Neurosci 71:13–24
Cai W, Zhang Y, Liu Y, Liu H, Zhang Z, Su Z (2019) Effects of miR-150 on neuropathic pain process via targeting AKT3. Biochem Biophys Res Commun 517:532–537
Catricala S, Torti M, Ricevuti G (2012) Alzheimer disease and platelets: how’s that relevant. Immunity Ageing 9:20
Celsis P (2000) Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer’s disease? Ann Med 32:6–14
Chen L, Sun H, Wang C, Yang Y, Zhang M, Wong G (2018) miRNA arm switching identifies novel tumour biomarkers. EBioMedicine 38:37–46
Coen RF, Robertson DA, Kenny RA, King-Kallimanis BL (2016) Strengths and limitations of the MoCA for assessing cognitive functioning: Findings from a large representative sample of Irish older adults. J Geriatr Psychiatry Neurol 29:18–24
Cui H, Xu Z, Qu C (2020) Tetramethylpyrazine ameliorates isoflurane induced cognitive dysfunction by inhibiting neuroinflammation via miR 150 in rats. Exp Therap Med 20:3878–3887
Dement A (2016) Alzheimer’s disease facts and figures. Alzheimer’s Dementia 12:459–509
Dolgin E (2018) Alzheimer’s disease is getting easier to spot. Nature 559:S10
Dostal DE, Rothblum KN, Baker KM (1994) An improved method for absolute quantification of mRNA using multiplex polymerase chain reaction: determination of renin and angiotensinogen mRNA levels in various tissues. Anal Biochem 223:239–250
Geekiyanage H, Jicha GA, Nelson PT, Chan C (2012) Blood serum miRNA: non-invasive biomarkers for Alzheimer’s disease. Exp Neurol 235:491–496
Griffiths-Jones S, Hui JH, Marco A, Ronshaugen M (2011) MicroRNA evolution by arm switching. EMBO Rep 12:172–177
Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR Jr, Galasko DR, Doody R (2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 61:59–66
Hébert SS, De Strooper B (2009) Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci 32:199–206
Hohman TJ, Tommet D, Marks S, Contreras J, Jones R, Mungas D, Alzheimer’s Neuroimaging Initiative (2017) Evaluating Alzheimer’s disease biomarkers as mediators of age-related cognitive decline. Neurobiol Aging 58:120–128
Ji L, Shi J, Lu J, Huang Q (2018) MiR-150 alleviates neuropathic pain via inhibiting toll‐like receptor 5. J Cell Biochem 119:1017–1026
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488:96–99
Junn E, Mouradian MM (2012) MicroRNAs in neurodegenerative diseases and their therapeutic potential. Pharmacol Ther 133:142–150
Keshavan A, Heslegrave A, Zetterberg H, Schott JM (2017) Blood biomarkers for Alzheimer’s disease: much promise cautious progress. Mol Diagn Ther 21:13–22
Kondkar AA, Bray MS, Leal SM, Nagalla S, Liu DJ, Jin Y, Dong JF, Ren Q, Whiteheart SW, Shaw C (2010) VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J Thromb Haemostat 8:369–378
Koychev I, Gunn RN, Firouzian A, Lawson J, Zamboni G, Ridha B, Sahakian BJ, Rowe JB, Thomas A, Rochester L (2017) PET tau and amyloid-β burden in mild Alzheimer’s disease: divergent relationship with age, cognition, and cerebrospinal fluid biomarkers. J Alzheimer’s Dis 60:283–293
Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P (2009) Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 16:961
Lau P, Bossers K, Salta E, Frigerio CS, Barbash S, Rothman R, Sierksma AS, Thathiah A, Greenberg D, Papadopoulou AS (2013) Alteration of the microRNA network during the progression of Alzheimer’s disease. EBMO Mol Med 5:1613–1634
Leidinger P, Backes C, Meder B, Meese E, Keller A (2014) The human miRNA repertoire of different blood compounds. BMC Genom 15:474
Levine ME, Lu AT, Bennett DA, Horvath S (2015) Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging(Albany, NY) 7:1198
Liang L, Zheng YW, Wang YL (2020) miR-4429 Regulates the proliferation, migration, invasion, and epithelial-mesenchymal transition of cervical cancer by targeting FOXM1. Cancer Mang Res 12:5301
Liu C, Wang J, Li L, Wang P (2014) MicroRNA-384 regulates both amyloid precursor protein and β-secretase expression and is a potential biomarker for Alzheimer’s disease. Int J Mol Med 34:160–166
Lopez-Ramirez MA, Reijerkerk A, De Vries HE, Romero IA (2016) Regulation of brain endothelial barrier function by microRNAs in health neuroinflammation. FASEB J 30:2662–2672
Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C, Rheinheimer S, Meder B, Stähler C, Meese E (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44:3865–3877
Lugli G, Cohen AM, Bennett DA, Shah RC, Fields CJ, Hernandez AG, Smalheiser NR (2015) Plasma exosomal miRNAs in persons with and without Alzheimer disease: altered expression and prospects for biomarkers. PLos One 10:e0139233
Lyketsos CG (2006) Task Force of American Association for Geriatric Psychiatry. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry 14:561–572
Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka S, van der Flier, Wiesje M, Blankenstein MA, Ewers M (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302:385–393
Mattsson N, Rosen E, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka S, Van Der Flier WM, Blankenstein MA, Ewers M (2012) Age and diagnostic performance of Alzheimer disease. CSF Biomark 78:468–476
Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L (2001) Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58:397–405
Murray MJ, Bell E, Raby KL, Rijlaarsdam MA, Gillis AJ, Looijenga LH, Brown H, Destenaves B, Nicholson JC, Coleman N (2016) A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. Br J Cancer 114:151–162
Nagalla S, Shaw C, Kong X, Kondkar AA, Edelstein LC, Ma L, Chen J, McKnight GS, López JA, Yang L (2011) Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 117:5189–5197
Nelson PT, Wang W, Rajeev BW (2008) MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 18:130–138
Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992
Riancho J, Vázquez-Higuera JL, Pozueta A, Lage C, Kazimierczak M, Bravo M, Calero M, Gonalezález A, Rodríguez E, Lleo A (2017) MicroRNA profile in patients with Alzheimer’s disease: analysis of miR-9-5p and miR-598 in raw and exosome enriched cerebrospinal fluid samples. J Alzheimer’s Dis 57:483–491
Rinnerthaler G, Hackl H, Gampenrieder SP, Hamacher F, Hufnagl C, Hauser-Kronberger C, Zehentmayr F, Fastner G, Sedlmayer F, Mlineritsch B (2016) miR-16-5p is a stably-expressed housekeeping microRNA in breast cancer tissues from primary tumors and from metastatic sites. Int J Mol Sci 17:156
Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J, Müller M (2011) pROC: an open-source package for R and S to analyze and compare ROC curves. BMC Bioinformatics 12:77
Schmand B, Eikelenboom P, Van Gool WA, Alzheimer’s Disease Neuroimaging Initiative (2011) Value of neuropsychological tests, neuroimaging, and biomarkers for diagnosing Alzheimer’s disease in younger and older age cohorts. J Am Geriatr Soc 59:1705–1710
Sevush S, Jy W, Horstman LL, Mao W, Kolodny L, Ahn YS (1998) Platelet activation in Alzheimer disease. Arch Neurol 55:530–536
Sinha M, Ghose J, Bhattarcharyya NP (2011) Micro RNA-214,-150,-146a and-125b target. Huntingtin Gene 8:1005–1021
Stewart S, O’Riley A, Edelstein B, Gould C (2012a) A preliminary comparison of three cognitive screening instruments in long term care: The MMSE, SLUMS, and MoCA. Clin Gerontol 35:57–75
Stewart S, O’Riley A, Edelstein B, Gould C (2012b) A preliminary comparison of three cognitive screening instruments in long term care: The MMSE, SLUMS, and MoCA. Clin Gerontol 35:57–75
Sun H, Chen Y (2019) MicroRNA expression profiles across blood and different tissues in cattle. Sci Data 6:190013
Vos SJ, Van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund L, Hampel H, Tsolaki M, Minthon L, Frisoni GB (2013) Prediction of Alzheimer disease in subjects with amnestic and nonamnestic. MCI 80:1124–1132
Voyle N, Baker D, Burnham SC, Covin A, Zhang Z, Sangurdekar DP, Tan Hehir CA, Bazenet C, Lovestone S, Kiddle S (2015) Blood protein markers of neocortical amyloid-β burden: a candidate study using SOMAscan technology. J Alzheimer’s Dis 46:947–961
Acknowledgements
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (2016R1C1B2007025) and by the National Dementia Research and Development Program of the Korea Health Industry Development Institute (KHIDI) funded by the Korean government (Ministry of Health and Welfare) (HI18C1671).
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Jae-Woong Min, Jina Lee, Hui-Jin Mun, Dae Hoon Kim, Byeong-Gyu Park, Bora Yoon, Jin-Hyeob Ryu, and Hyun-Jeong Cho declare that they have no conflicts of interest.
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Min, JW., Lee, J., Mun, HJ. et al. Diagnostic and therapeutic biomarkers for Alzheimer’s disease in human-derived platelets. Genes Genom 42, 1467–1475 (2020). https://doi.org/10.1007/s13258-020-01015-6
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DOI: https://doi.org/10.1007/s13258-020-01015-6