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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

miRNA-Based Signature to Predict the Development of Alzheimer’s Disease

Author(s): Fangfang Zhan, Jinshan Yang, Shifang Lin and Longfei Chen*

Volume 25, Issue 12, 2022

Published on: 07 March, 2022

Page: [2103 - 2111] Pages: 9

DOI: 10.2174/1386207325666220208122911

Price: $65

Abstract

Background: Patients with mild cognitive impairment (MCI) suffer from a high risk of developing Alzheimer’s disease (AD). Cumulative evidence has demonstrated that the development of AD is a complex process that could be modulated by miRNAs. Here, we aimed to identify miRNAs involved in the pathway, and interrogate their ability to predict prognosis in patients with MCI.

Methods: We obtained the miRNA-seq profiles and the clinical characteristics of patients with MCI from the Gene Expression Omnibus (GEO). Cox regression analysis was used to construct a risk level model. The receiver operating characteristic (ROC) curve was used to assess the performance of the model for predicting prognosis. Combined with clinical characteristics, factors associated with prognosis were identified and a predictive prognosis nomogram was developed and validated. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we evaluated molecular signatures for the candidate miRNAs.

Results: Our analysis identified 120 DEmiRNAs. The Cox regression analysis showed that two miRNAs could serve as risk factors for disease development. A risk level model was constructed. Age, apoe4, and risk level were associated with the prognosis. We developed a nomogram to predict disease progression. The calibration curve and concordance index (C-index) demonstrated the reliability of the nomogram. Functional enrichment analysis showed that these miRNAs were involved in regulating both cGMP-PKG and Sphingolipid signaling pathways.

Conclusion: We have identified miRNAs associated with the development of MCI. These miRNAs could be used for early diagnosis and surveillance in patients with MCI, enabling prediction of the development of AD.

Keywords: Alzheimer’s disease, mild cognitive impairment, miRNAs, nomogram, prognosis, diagnosis.

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[1]
Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol., 2018, 25(1), 59-70.
[http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]
[2]
Kukull, W.A.; Bowen, J.D. Dementia epidemiology. Med. Clin. North Am., 2002, 86(3), 573-590.
[http://dx.doi.org/10.1016/S0025-7125(02)00010-X] [PMID: 12168560]
[3]
Sherrington, R.; Rogaev, E.I.; Liang, Y.; Rogaeva, E.A.; Levesque, G.; Ikeda, M.; Chi, H.; Lin, C.; Li, G.; Holman, K.; Tsuda, T.; Mar, L.; Foncin, J.F.; Bruni, A.C.; Montesi, M.P.; Sorbi, S.; Rainero, I.; Pinessi, L.; Nee, L.; Chumakov, I.; Pollen, D.; Brookes, A.; Sanseau, P.; Po-linsky, R.J.; Wasco, W.; Da Silva, H.A.; Haines, J.L.; Perkicak-Vance, M.A.; Tanzi, R.E.; Roses, A.D.; Fraser, P.E.; Rommens, J.M.; St George-Hyslop, P.H. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 1995, 375(6534), 754-760.
[http://dx.doi.org/10.1038/375754a0] [PMID: 7596406]
[4]
Goate, A.; Chartier-Harlin, M.C.; Mullan, M.; Brown, J.; Crawford, F.; Fidani, L.; Giuffra, L.; Haynes, A.; Irving, N.; James, L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 1991, 349(6311), 704-706.
[http://dx.doi.org/10.1038/349704a0] [PMID: 1671712]
[5]
Uddin, M.S.; Kabir, M.T.; Al Mamun, A.; Abdel-Daim, M.M.; Barreto, G.E.; Ashraf, G.M. APOE and Alzheimer’s Disease: Evidence mounts that targeting APOE4 may combat Alzheimer’s Pathogenesis. Mol. Neurobiol., 2019, 56(4), 2450-2465.
[http://dx.doi.org/10.1007/s12035-018-1237-z] [PMID: 30032423]
[6]
Ulland, T.K.; Colonna, M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol., 2018, 14(11), 667-675.
[http://dx.doi.org/10.1038/s41582-018-0072-1] [PMID: 30266932]
[7]
Zhou, Y.; Ulland, T.K.; Colonna, M. TREM2-dependent effects on microglia in Alzheimer’s Disease. Front. Aging Neurosci., 2018, 10, 202.
[http://dx.doi.org/10.3389/fnagi.2018.00202] [PMID: 30038567]
[8]
Reitz, C. Genetic diagnosis and prognosis of Alzheimer’s disease: challenges and opportunities. Expert Rev. Mol. Diagn., 2015, 15(3), 339-348.
[http://dx.doi.org/10.1586/14737159.2015.1002469] [PMID: 25634383]
[9]
De Felice, B.; Montanino, C.; Oliva, M.; Bonavita, S.; Di Onofrio, V.; Coppola, C. MicroRNA expression signature in mild cognitive im-pairment due to Alzheimer’s disease. Mol. Neurobiol., 2020, 57(11), 4408-4416.
[http://dx.doi.org/10.1007/s12035-020-02029-7] [PMID: 32737762]
[10]
Silvestro, S.; Bramanti, P.; Mazzon, E. Role of miRNAs in Alzheimer’s disease and possible fields of application. Int. J. Mol. Sci., 2019, 20(16), E3979.
[http://dx.doi.org/10.3390/ijms20163979] [PMID: 31443326]
[11]
Reddy, P.H.; Tonk, S.; Kumar, S.; Vijayan, M.; Kandimalla, R.; Kuruva, C.S.; Reddy, A.P. A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer’s disease. Biochem. Biophys. Res. Commun., 2017, 483(4), 1156-1165.
[http://dx.doi.org/10.1016/j.bbrc.2016.08.067] [PMID: 27524239]
[12]
Kumar, S.; Vijayan, M.; Reddy, P.H. MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer’s disease. Hum. Mol. Genet., 2017, 26(19), 3808-3822.
[http://dx.doi.org/10.1093/hmg/ddx267] [PMID: 28934394]
[13]
Smith, P.; Al Hashimi, A.; Girard, J.; Delay, C.; Hébert, S.S. In vivo regulation of amyloid precursor protein neuronal splicing by mi-croRNAs. J. Neurochem., 2011, 116(2), 240-247.
[http://dx.doi.org/10.1111/j.1471-4159.2010.07097.x] [PMID: 21062284]
[14]
Fang, M.; Wang, J.; Zhang, X.; Geng, Y.; Hu, Z.; Rudd, J.A.; Ling, S.; Chen, W.; Han, S. The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer’s disease. Toxicol. Lett., 2012, 209(1), 94-105.
[http://dx.doi.org/10.1016/j.toxlet.2011.11.032] [PMID: 22178568]
[15]
Augustin, R.; Endres, K.; Reinhardt, S.; Kuhn, P-H.; Lichtenthaler, S.F.; Hansen, J.; Wurst, W.; Trümbach, D. Computational identification and experimental validation of microRNAs binding to the Alzheimer-related gene ADAM10. BMC Med. Genet., 2012, 13, 35.
[http://dx.doi.org/10.1186/1471-2350-13-35] [PMID: 22594617]
[16]
Krichevsky, A.M.; King, K.S.; Donahue, C.P.; Khrapko, K.; Kosik, K.S. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA, 2003, 9(10), 1274-1281.
[http://dx.doi.org/10.1261/rna.5980303] [PMID: 13130141]
[17]
Hébert, S.S.; Papadopoulou, A.S.; Smith, P.; Galas, M-C.; Planel, E.; Silahtaroglu, A.N.; Sergeant, N.; Buée, L.; De Strooper, B. Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum. Mol. Genet., 2010, 19(20), 3959-3969.
[http://dx.doi.org/10.1093/hmg/ddq311] [PMID: 20660113]
[18]
Carrettiero, D.C.; Hernandez, I.; Neveu, P.; Papagiannakopoulos, T.; Kosik, K.S. The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. J. Neurosci., 2009, 29(7), 2151-2161.
[http://dx.doi.org/10.1523/JNEUROSCI.4660-08.2009] [PMID: 19228967]
[19]
Kim, J.; Yoon, H.; Horie, T.; Burchett, J.M.; Restivo, J.L.; Rotllan, N.; Ramírez, C.M.; Verghese, P.B.; Ihara, M.; Hoe, H.S.; Esau, C. Fer-nández-Hernando, C.; Holtzman, D.M.; Cirrito, J.R.; Ono, K.; Kim, J. microRNA-33 regulates ApoE lipidation and amyloid-β metabolism in the brain. J. Neurosci., 2015, 35(44), 14717-14726.
[http://dx.doi.org/10.1523/JNEUROSCI.2053-15.2015] [PMID: 26538644]
[20]
Sheinerman, K.S.; Tsivinsky, V.G.; Abdullah, L.; Crawford, F.; Umansky, S.R. Plasma microRNA biomarkers for detection of mild cogni-tive impairment: biomarker validation study. Aging (Albany NY), 2013, 5(12), 925-938.
[http://dx.doi.org/10.18632/aging.100624] [PMID: 24368295]
[21]
Smith, P.Y.; Hernandez-Rapp, J.; Jolivette, F.; Lecours, C.; Bisht, K.; Goupil, C.; Dorval, V.; Parsi, S.; Morin, F.; Planel, E.; Bennett, D.A.; Fernandez-Gomez, F.J.; Sergeant, N.; Buée, L.; Tremblay, M.È.; Calon, F.; Hébert, S.S. miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo. Hum. Mol. Genet., 2015, 24(23), 6721-6735.
[http://dx.doi.org/10.1093/hmg/ddv377] [PMID: 26362250]
[22]
Salta, E.; Sierksma, A.; Vanden Eynden, E.; De Strooper, B. miR-132 loss de-represses ITPKB and aggravates amyloid and TAU patholo-gy in Alzheimer’s brain. EMBO Mol. Med., 2016, 8(9), 1005-1018.
[http://dx.doi.org/10.15252/emmm.201606520] [PMID: 27485122]
[23]
Shigemizu, D.; Akiyama, S.; Higaki, S.; Sugimoto, T.; Sakurai, T.; Boroevich, K.A.; Sharma, A.; Tsunoda, T.; Ochiya, T.; Niida, S.; Ozaki, K. Prognosis prediction model for conversion from mild cognitive impairment to Alzheimer’s disease created by integrative analysis of multi-omics data. Alzheimers Res. Ther., 2020, 12(1), 145.
[http://dx.doi.org/10.1186/s13195-020-00716-0] [PMID: 33172501]
[24]
Kasper, S.; Bancher, C.; Eckert, A.; Förstl, H.; Frölich, L.; Hort, J.; Korczyn, A.D.; Kressig, R.W.; Levin, O.; Palomo, M.S.M. Management of mild cognitive impairment (MCI): The need for national and international guidelines. World J. Biol. Psychiatry, 2020, 21(8), 579-594.
[http://dx.doi.org/10.1080/15622975.2019.1696473] [PMID: 32019392]
[25]
Vos, S.J.B.; Verhey, F.; Frölich, L.; Kornhuber, J.; Wiltfang, J.; Maier, W.; Peters, O.; Rüther, E.; Nobili, F.; Morbelli, S.; Frisoni, G.B.; Drzezga, A.; Didic, M.; van Berckel, B.N.; Simmons, A.; Soininen, H.; Kłoszewska, I.; Mecocci, P.; Tsolaki, M.; Vellas, B.; Lovestone, S.; Muscio, C.; Herukka, S.K.; Salmon, E.; Bastin, C.; Wallin, A.; Nordlund, A.; de Mendonça, A.; Silva, D.; Santana, I.; Lemos, R.; Engelbor-ghs, S.; Van der Mussele, S.; Freund-Levi, Y.; Wallin, Å.K.; Hampel, H.; van der Flier, W.; Scheltens, P.; Visser, P.J. Alzheimer’s Disease Neuroimaging Initiative. Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain, 2015, 138(Pt 5), 1327-1338.
[http://dx.doi.org/10.1093/brain/awv029] [PMID: 25693589]
[26]
López Trigo, J.A. Consensus document. Mild cognitive impairment. Detection and management. A public health challenge. Rev. Esp. Geriatr. Gerontol., 2017, 52(Suppl. 1), 1-2.
[PMID: 29628026]
[27]
van Maurik, I.S.; Zwan, M.D.; Tijms, B.M.; Bouwman, F.H.; Teunissen, C.E.; Scheltens, P.; Wattjes, M.P.; Barkhof, F.; Berkhof, J.; van der Flier, W.M. Alzheimer’s disease neuroimaging initiative. Interpreting biomarker results in individual patients with mild cognitive im-pairment in the Alzheimer’s biomarkers in daily practice (ABIDE) project. JAMA Neurol., 2017, 74(12), 1481-1491.
[http://dx.doi.org/10.1001/jamaneurol.2017.2712] [PMID: 29049480]
[28]
Grasso, M.; Piscopo, P.; Confaloni, A.; Denti, M.A. Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules, 2014, 19(5), 6891-6910.
[http://dx.doi.org/10.3390/molecules19056891] [PMID: 24858274]
[29]
Ansari, A.; Maffioletti, E.; Milanesi, E.; Marizzoni, M.; Frisoni, G.B.; Blin, O.; Richardson, J.C.; Bordet, R.; Forloni, G.; Gennarelli, M.; Bocchio-Chiavetto, L. PharmaCog Consortium. miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer’s disease. Neurobiol. Aging, 2019, 82, 102-109.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.005] [PMID: 31437718]
[30]
Liu, C-G.; Wang, J-L.; Li, L.; Wang, P-C. MicroRNA-384 regulates both amyloid precursor protein and β-secretase expression and is a potential biomarker for Alzheimer’s disease. Int. J. Mol. Med., 2014, 34(1), 160-166.
[http://dx.doi.org/10.3892/ijmm.2014.1780] [PMID: 24827165]
[31]
Liu, D.Y.; Zhang, L. MicroRNA-132 promotes neurons cell apoptosis and activates Tau phosphorylation by targeting GTDC-1 in Alz-heimer’s disease. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(19), 8523-8532.
[PMID: 31646584]
[32]
Van Giau, V.; An, S.S.A. Emergence of exosomal miRNAs as a diagnostic biomarker for Alzheimer’s disease. J. Neurol. Sci., 2016, 360, 141-152.
[http://dx.doi.org/10.1016/j.jns.2015.12.005] [PMID: 26723991]
[33]
Li, W.; Li, X.; Xin, X.; Kan, P-C.; Yan, Y. MicroRNA-613 regulates the expression of brain-derived neurotrophic factor in Alzheimer’s disease. Biosci. Trends, 2016, 10(5), 372-377.
[http://dx.doi.org/10.5582/bst.2016.01127] [PMID: 27545218]
[34]
Wang, W-X.; Rajeev, B.W.; Stromberg, A.J.; Ren, N.; Tang, G.; Huang, Q.; Rigoutsos, I.; Nelson, P.T. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor pro-tein-cleaving enzyme 1. J. Neurosci., 2008, 28(5), 1213-1223.
[http://dx.doi.org/10.1523/JNEUROSCI.5065-07.2008] [PMID: 18234899]
[35]
Ferrari, R.; Grassi, M.; Salvi, E.; Borroni, B.; Palluzzi, F.; Pepe, D. A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia. Neurobiol. Aging, 2015, 36(10), e13-e26.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.06.005]
[36]
Ferrari, R.; Manzoni, C.; Hardy, J. Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future ave-nues. Neurobiol. Aging, 2019, 78, 98-110.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.02.006] [PMID: 30925302]
[37]
LU. F. Expressions of microRNA-1250 and its host gene AATK and AATK gene methylation status in human esophageal squamous cell carcinoma. Tumor, 2017, 483-490.
[38]
Zhang, M.Y.; Wang, L.Q.; Chim, C.S. miR-1250-5p is a novel tumor suppressive intronic miRNA hypermethylated in non-Hodgkin’s lymphoma: novel targets with impact on ERK signaling and cell migration. Cell Commun. Signal., 2021, 19(1), 62.
[http://dx.doi.org/10.1186/s12964-021-00707-0] [PMID: 34044822]
[39]
Liu, L.; Xu, H.; Ding, S.; Wang, D.; Song, G.; Huang, X. Phosphodiesterase 5 inhibitors as novel agents for the treatment of Alzheimer’s disease. Brain Res. Bull., 2019, 153, 223-231.
[http://dx.doi.org/10.1016/j.brainresbull.2019.09.001] [PMID: 31493542]
[40]
Fang, Y.; Su, Z.; Si, W.; Liu, Y.; Li, J.; Zeng, P. Network pharmacology-based study of the therapeutic mechanism of resveratrol for Alz-heimer’s disease. Nan Fang Yi Ke Da Xue Xue Bao, 2021, 41(1), 10-19.
[PMID: 33509748]
[41]
Mielke, M.M.; Lyketsos, C.G. Alterations of the sphingolipid pathway in Alzheimer’s disease: new biomarkers and treatment targets? Neuromolecular Med., 2010, 12(4), 331-340.
[http://dx.doi.org/10.1007/s12017-010-8121-y] [PMID: 20571935]
[42]
Walgrave, H.; Zhou, L.; De Strooper, B.; Salta, E. The promise of microRNA-based therapies in Alzheimer’s disease: challenges and per-spectives. Mol. Neurodegener., 2021, 16(1), 76.
[http://dx.doi.org/10.1186/s13024-021-00496-7] [PMID: 34742333]

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