MiR-129-5p As a Biomarker for Pathology and Cognitive Decline in Alzheimer's Disease

Overview

Journal Res Sq

Date 2023 Nov 14

PMID 37961387

Authors

Sang-Won Han

Jung-Min Pyun

Paula J Bice

David A Bennett

Andrew J Saykin

SangYun Kim

Young Ho Park

Kwangsik Nho

Affiliations

Soon will be listed here.

Abstract

Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers.

Methods: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset. We performed association analysis of hub miRNAs with AD, its neuropathology markers, and cognition. After selecting target genes of the hub miRNAs, we performed association analysis of the hub miRNAs with their target genes and then performed pathway-based enrichment analysis. For replication, we performed a consensus miRNA co-expression network analysis using the ROS/MAP dataset and an independent dataset (N = 16) from the Gene Expression Omnibus (GEO). Furthermore, we performed a machine learning approach to assess the performance of hub miRNAs for AD classification.

Results: Network analysis identified a glucose metabolism pathway-enriched module (M3) as significantly associated with AD and cognition. Five hub miRNAs (miR-129-5p, miR-433, miR-1260, miR-200a, and miR-221) of M3 had significant associations with AD clinical and/or pathologic traits, with miR129-5p by far the strongest across all phenotypes. Gene-set enrichment analysis of target genes associated with their corresponding hub miRNAs identified significantly enriched biological pathways including ErbB, AMPK, MAPK, and mTOR signaling pathways. Consensus network analysis identified two AD-associated consensus network modules, and two hub miRNAs (miR-129-5p and miR-221). Machine learning analysis showed that the AD classification performance (area under the curve (AUC) = 0.807) of age, sex, and ε4 carrier status was significantly improved by 6.3% with inclusion of five AD-associated hub miRNAs.

Conclusions: Integrative network and machine learning analysis identified miRNA signatures, especially miR-129-5p, as associated with AD, its neuropathology markers, and cognition, enhancing our understanding of AD pathogenesis and leading to better performance of AD classification as potential diagnostic/prognostic biomarkers.

References

Liu D, Tang H, Li X, Deng M, Wei N, Wang X . Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease. Mol Ther. 2017; 25(3):752-764. PMC: 5363202. DOI: 10.1016/j.ymthe.2017.01.018. View

Schneider J, Arvanitakis Z, Bang W, Bennett D . Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007; 69(24):2197-204. DOI: 10.1212/01.wnl.0000271090.28148.24. View

Bennett D, Schneider J, Arvanitakis Z, Kelly J, Aggarwal N, Shah R . Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006; 66(12):1837-44. DOI: 10.1212/01.wnl.0000219668.47116.e6. View

Barbato C, Giacovazzo G, Albiero F, Scardigli R, Scopa C, Ciotti M . Cognitive Decline and Modulation of Alzheimer's Disease-Related Genes After Inhibition of MicroRNA-101 in Mouse Hippocampal Neurons. Mol Neurobiol. 2020; 57(7):3183-3194. DOI: 10.1007/s12035-020-01957-8. View

Li J, Han X, Wan Y, Zhang S, Zhao Y, Fan R . TAM 2.0: tool for MicroRNA set analysis. Nucleic Acids Res. 2018; 46(W1):W180-W185. PMC: 6031048. DOI: 10.1093/nar/gky509. View

Li Q, Wang Y, Peng W, Jia Y, Tang J, Li W . MicroRNA-101a Regulates Autophagy Phenomenon via the MAPK Pathway to Modulate Alzheimer's-Associated Pathogenesis. Cell Transplant. 2019; 28(8):1076-1084. PMC: 6728707. DOI: 10.1177/0963689719857085. View

Angelucci F, Cechova K, Valis M, Kuca K, Zhang B, Hort J . MicroRNAs in Alzheimer's Disease: Diagnostic Markers or Therapeutic Agents?. Front Pharmacol. 2019; 10:665. PMC: 6591466. DOI: 10.3389/fphar.2019.00665. View

Zhang Y, Bao H, Dong L, Liu Y, Zhang G, An F . Silenced lncRNA H19 and up-regulated microRNA-129 accelerates viability and restrains apoptosis of PC12 cells induced by Aβ in a cellular model of Alzheimer's disease. Cell Cycle. 2021; 20(1):112-125. PMC: 7849745. DOI: 10.1080/15384101.2020.1863681. View

Nam J, Rissland O, Koppstein D, Abreu-Goodger C, Jan C, Agarwal V . Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell. 2014; 53(6):1031-1043. PMC: 4062300. DOI: 10.1016/j.molcel.2014.02.013. View

10.

Liu S, Fan M, Zheng Q, Hao S, Yang L, Xia Q . MicroRNAs in Alzheimer's disease: Potential diagnostic markers and therapeutic targets. Biomed Pharmacother. 2022; 148:112681. DOI: 10.1016/j.biopha.2022.112681. View

11.

Wang R, Zhang J . Clinical significance of miR-433 in the diagnosis of Alzheimer's disease and its effect on Aβ-induced neurotoxicity by regulating JAK2. Exp Gerontol. 2020; 141:111080. DOI: 10.1016/j.exger.2020.111080. View

12.

Li S, Yan Y, Jiao Y, Gao Z, Xia Y, Kong L . Neuroprotective Effect of Osthole on Neuron Synapses in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9. J Mol Neurosci. 2016; 60(1):71-81. DOI: 10.1007/s12031-016-0793-9. View

13.

Mirra S, HEYMAN A, McKeel D, SUMI S, Crain B, Brownlee L . The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991; 41(4):479-86. DOI: 10.1212/wnl.41.4.479. View

14.

. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 2012; 8(2):131-68. DOI: 10.1016/j.jalz.2012.02.001. View

15.

Manzine P, Pelucchi S, Horst M, Vale F, Pavarini S, Audano M . microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. J Alzheimers Dis. 2017; 61(1):113-123. DOI: 10.3233/JAD-170592. View

16.

Lau P, Bossers K, Janky R, Salta E, Sala Frigerio C, Barbash S . Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol Med. 2013; 5(10):1613-34. PMC: 3799583. DOI: 10.1002/emmm.201201974. View

17.

Bennett D, Schneider J, Bienias J, Evans D, Wilson R . Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology. 2005; 64(5):834-41. DOI: 10.1212/01.WNL.0000152982.47274.9E. View

18.

Kozomara A, Griffiths-Jones S . miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2013; 42(Database issue):D68-73. PMC: 3965103. DOI: 10.1093/nar/gkt1181. View

19.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

20.

Wong N, Wang X . miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2014; 43(Database issue):D146-52. PMC: 4383922. DOI: 10.1093/nar/gku1104. View