A single nucleotide polymorphism in primary‑microRNA‑146a reduces the expression of mature microRNA‑146a in patients with Alzheimer's disease and is associated with the pathogenesis of Alzheimer's disease

Zhang,Bin; Wang,Aihong; Xia,Cuiping; Lin,Qunfeng; Chen,Chunfu

doi:10.3892/mmr.2015.3968

A single nucleotide polymorphism in primary‑microRNA‑146a reduces the expression of mature microRNA‑146a in patients with Alzheimer's disease and is associated with the pathogenesis of Alzheimer's disease

Authors:
- Bin Zhang
- Aihong Wang
- Cuiping Xia
- Qunfeng Lin
- Chunfu Chen
View Affiliations

Affiliations: Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Neurology, Shanghai Fengxian Central Hospital, Shanghai 201499, P.R. China
Published online on: June 22, 2015 https://doi.org/10.3892/mmr.2015.3968
Pages: 4037-4042
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia among the aging population. Although the incidence of the disease continues to increase, no cure has been developed. Effective treatment is restricted not only due to the lack of curative medicine, but also due to limited understanding of the underlying mechanisms and the difficulties in accurately diagnosing AD in its earliest stages prior to clinical symptoms. Micro (mi) RNAs (miR) have gained increasing attention in the investigation of neurodegenerative diseases. Previous reports have demonstrated that deregulation of miR‑146a‑5p is associated with the pathogenesis of human AD. In the present study, the coding region of primary (pri)‑miR‑146a in patients with AD was scanned and the rare C allele of rs2910164 was found to be associated with AD. Using reverse transcription quantitative polymerase chain reaction, it was demonstrated that site variation reduced the expression of mature miR‑146a‑5p. Notably, a reduction in the expression of miR‑146a‑5p led to less efficient inhibition of target genes, including Toll‑like receptor (TLR)2, which is important in the pathogenesis of AD. Biological function investigations in RAW264.7 cells indicated that, compared with the G allele, the rare C allele upregulated the expression of tumor necrosis factor‑α following stimulation with β‑amyloid. These findings suggested that one common polymorphism in pri‑miR‑146a may contribute to the genetic predisposition to AD by disrupting the production of miR‑146a‑5p and affecting the expression and function of TLR2.

View Figures

View References

1	Van den Hove DL, Kompotis K, Lardenoije R, Kenis G, Mill J, Steinbusch HW, Lesch KP, Fitzsimons CP, De Strooper B and Rutten BP: Epigenetically regulated microRNAs in Alzheimer's disease. Neurobiol Aging. 35:731–745. 2014. View Article : Google Scholar
2	Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, et al: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 400:173–177. 1999. View Article : Google Scholar : PubMed/NCBI
3	Machado A, Herrera AJ, de Pablos RM, Espinosa-Oliva AM, Sarmiento M, Ayala A, Venero JL, Santiago M, Villarán RF, Delgado-Cortés MJ, et al: Chronic stress as a risk factor for Alzheimer's disease. Rev Neurosci. 25:785–804. 2014. View Article : Google Scholar : PubMed/NCBI
4	Karch CM, Cruchaga C and Goate AM: Alzheimer's disease genetics: From the bench to the clinic. Neuron. 83:11–26. 2014. View Article : Google Scholar : PubMed/NCBI
5	Morales I, Farías G and Maccioni RB: Neuroimmunomodulation in the pathogenesis of Alzheimer's disease. Neuroimmunomodulation. 17:202–204. 2010. View Article : Google Scholar : PubMed/NCBI
6	Hickman SE and El Khoury J: The neuroimmune system in Alzheimer's disease: The glass is half full. J Alzheimers Dis. 33(Suppl 1): S295–S302. 2013.
7	Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rübe CE, Walter J, Heneka MT, Hartmann T, et al: TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory activation. J Immunol. 188:1098–1107. 2012. View Article : Google Scholar
8	Masters CL and Beyreuther K: Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain. 129:2823–2839. 2006. View Article : Google Scholar : PubMed/NCBI
9	Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M and Calhoun ME: Dynamics of the microglial/amyloid interaction indicate a role in plaque main tenance. J Neurosci. 28:4283–4292. 2008. View Article : Google Scholar : PubMed/NCBI
10	Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ and Hyman BT: Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 451:720–724. 2008. View Article : Google Scholar : PubMed/NCBI
11	Jana M, Palencia CA and Pahan K: Fibrillar amyloid-beta peptides activate microglia via TLR2: Implications for Alzheimer's disease. J Immunol. 181:7254–7262. 2008. View Article : Google Scholar : PubMed/NCBI
12	Udan ML, Ajit D, Crouse NR and Nichols MR: Toll-like receptors 2 and 4 mediate Abeta (1–42) activation of the innate immune response in a human monocytic cell line. J Neurochem. 104:524–533. 2008.
13	Richard KL, Filali M, Préfontaine P and Rivest S: Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci. 28:5784–5793. 2008. View Article : Google Scholar : PubMed/NCBI
14	Zhang W, Wang LZ, Yu JT, Chi ZF and Tan L: Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer's disease. J Neurol Sci. 315:67–71. 2012. View Article : Google Scholar
15	Maes OC, Chertkow HM, Wang E and Schipper HM: MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders. Curr Genomics. 10:154–168. 2009. View Article : Google Scholar : PubMed/NCBI
16	Xu J, Li Y, Wang F, Wang X and Cheng B: Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene. 32:976–987. 2013. View Article : Google Scholar
17	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013. View Article : Google Scholar : PubMed/NCBI
18	Lukiw WJ, Zhao Y and Cui JG: An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 283:31315–31322. 2008. View Article : Google Scholar : PubMed/NCBI
19	Li YY, Cui JG, Hill JM, Bhattacharjee S, Zhao Y and Lukiw WJ: Increased expression of miRNA-146a in Alzheimer's disease transgenic mouse models. Neurosci Lett. 487:94–98. 2011. View Article : Google Scholar
20	Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR and de la Chapelle A: Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA. 105:7269–7274. 2008. View Article : Google Scholar : PubMed/NCBI
21	Betel D, Wilson M, Gabow A, Marks DS and Sander C: The microRNA.org resource: Targets and expression. Nucleic Acids Res. 36(Database): D149–D153. 2008. View Article : Google Scholar :
22	Ransohoff RM and Brown MA: Innate immunity in the central nervous system. J Clin Invest. 122:1164–1171. 2012. View Article : Google Scholar : PubMed/NCBI
23	Lynch MA: The impact of neuroimmune changes on development of amyloid pathology; relevance to Alzheimer's disease. Immunology. 141:292–301. 2014. View Article : Google Scholar :
24	Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M and Asahara H: Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58:1284–1292. 2008. View Article : Google Scholar : PubMed/NCBI
25	Sonkoly E, Wei T, Janson PC, Sääf A, Lundeberg L, Tengvall-Linder M, Norstedt G, Alenius H, Homey B, Scheynius A, et al: MicroRNAs: Novel regulators involved in the pathogenesis of psoriasis? PLoS One. 2:e6102007. View Article : Google Scholar : PubMed/NCBI
26	Sethi P and Lukiw WJ: Micro-RNA abundance and stability in human brain: Specific alterations in Alzheimer's disease temporal lobe neocortex. Neurosci Lett. 459:100–104. 2009. View Article : Google Scholar : PubMed/NCBI