Amyloid Beta 1–42 Alters the Expression of miRNAs in Cortical Neurons
Recently, Aβ1–42 was demonstrated to have the potential to translocate into the nucleus and to be involved in the transcriptional regulation of certain neurodegeneration-related genes. This data raises the question of whether Aβ-induced neurodegeneration might include the expression of miRNAs. Thus, our aim in this study was to investigate the effects of Aβ1–42 on certain miRNAs which are related with vitamin D metabolism, neuronal differentiation, development, and memory. This question was investigated in primary cortical neurons that were treated with 10 μM Aβ and/or 10–8 M 1,25-dihydroxyvitamin D3 at different time points by expression analysis of let-7a-5p, miR-26b-5p, miR-27b-3p, miR-31a-5p, miR-125b-5p, and miR-192-5p with qRT-PCR. Our data indicate that amyloid pathology has effects on the expression of miRNAs. Furthermore, some of these miRNAs simultaneously regulate the proteins or the enzymes involved in neuronal metabolism. The experimental setup that we used and the data we acquired supply valuable information about the miRNAs that play a part in the Aβ pathology and suggested Aβ as a counterpart of vitamin D at the crossroads of neuronal differentiation, development, and memory.
KeywordsAlzheimer’s disease Aβ Vitamin D Vitamin D receptor (VDR) miRNA
Conceived and designed the experiments: DGA and ED. Performed the experiments: DGA, ED, EC. Analyzed the data: DGA and ED. Drafted and revised the manuscript: DGA, SY, and ED. All authors reviewed the manuscript.
The present work was supported by the Research Fund of Istanbul University, Project no: 21585, and by the Scientific and Technological Research Council of Turkey-TUBITAK, Project no. 214S585.
Compliance with Ethical Standards
The study was approved by the Animal Welfare and Ethics Committee of Istanbul University with the numbers 26.07.2012/101, and procedures that involved experimentation on animal subjects were carried out in accordance with both the guide of Istanbul University and with the National Research Council’s guide for the care and use of laboratory animals.
Conflict of Interest
The authors declare that they have no conflict of interest.
The English of the manuscript has been edited by ELSEVIER Language Editing Service with the Reference Number: LE222898.
- Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19(13):2739–2745. https://doi.org/10.1093/hmg/ddq155 CrossRefPubMedPubMedCentralGoogle Scholar
- Annweiler C, Dursun E, Feron F, Gezen-Ak D, Kalueff AV, Littlejohns T, Llewellyn DJ, Millet P, Scott T, Tucker KL, Yilmazer S, Beauchet O (2015) ‘Vitamin D and cognition in older adults’: updated international recommendations. J Intern Med 277(1):45–57. https://doi.org/10.1111/joim.12279 CrossRefPubMedPubMedCentralGoogle Scholar
- Beydoun MA, Tajuddin SM, Dore GA, Canas JA, Beydoun HA, Evans MK, Zonderman AB (2017) Vitamin D receptor and megalin gene polymorphisms are associated with longitudinal cognitive change among African-American urban adults. J Nutr 147(6):1048–1062. https://doi.org/10.3945/jn.116.244962 CrossRefPubMedPubMedCentralGoogle Scholar
- Cataldi S, Arcuri C, Hunot S, Mecca C, Codini M, Laurenti ME, Ferri I, Loreti E, Garcia-Gil M, Traina G, Conte C, Ambesi-Impiombato FS, Beccari T, Curcio F, Albi E (2018) Effect of vitamin D in HN9.10e embryonic hippocampal cells and in hippocampus from MPTP-induced Parkinson’s disease mouse model. Front Cell Neurosci 12:31. https://doi.org/10.3389/fncel.2018.00031 CrossRefPubMedPubMedCentralGoogle Scholar
- Dursun E, Gezen-Ak D, Yilmazer S (2011) A novel perspective for disease: vitamin D receptor suppression by amyloid-beta and preventing the amyloid-beta induced alterations by vitamin D in cortical neurons. J Alzheimers Dis 23(2):207–219. https://doi.org/10.3233/JAD-2010-101377 CrossRefPubMedPubMedCentralGoogle Scholar
- Dursun E, Gezen-Ak D, Yilmazer S (2013a) Beta amyloid suppresses the expression of the vitamin d receptor gene and induces the expression of the vitamin d catabolic enzyme gene in hippocampal neurons. Dement Geriatr Cogn Disord 36(1–2):76–86. https://doi.org/10.1159/000350319 CrossRefPubMedPubMedCentralGoogle Scholar
- Dursun E, Alaylioglu M, Bilgic B, Hanagasi H, Lohmann E, Atasoy IL, Candas E, Araz OS, Onal B, Gurvit H, Yilmazer S, Gezen-Ak D (2016) Vitamin D deficiency might pose a greater risk for ApoEvarepsilon4 non-carrier Alzheimer’s disease patients. Neurol Sci 37(10):1633–1643. https://doi.org/10.1007/s10072-016-2647-1 CrossRefPubMedPubMedCentralGoogle Scholar
- El Fatimy R, Li S, Chen Z, Mushannen T, Gongala S, Wei Z, Balu DT, Rabinovsky R, Cantlon A, Elkhal A, Selkoe DJ, Sonntag KC, Walsh DM, Krichevsky AM (2018) MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways. Acta Neuropathol 136(4):537–555. https://doi.org/10.1007/s00401-018-1880-5 CrossRefPubMedPubMedCentralGoogle Scholar
- Feng MG, Liu CF, Chen L, Feng WB, Liu M, Hai H, Lu JM (2018) MiR-21 attenuates apoptosis-triggered by amyloid-beta via modulating PDCD4/ PI3K/AKT/GSK-3beta pathway in SH-SY5Y cells. Biomed Pharmacother 101:1003–1007. https://doi.org/10.1016/j.biopha.2018.02.043 CrossRefPubMedPubMedCentralGoogle Scholar
- Georges SA, Biery MC, Kim SY, Schelter JM, Guo J, Chang AN, Jackson AL, Carleton MO, Linsley PS, Cleary MA, Chau BN (2008) Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215. Cancer Res 68(24):10105–10112. https://doi.org/10.1158/0008-5472.CAN-08-1846 CrossRefPubMedPubMedCentralGoogle Scholar
- Gezen-Ak D, Alaylioglu M, Genc G, Gunduz A, Candas E, Bilgic B, Atasoy IL, Apaydin H, Kiziltan G, Gurvit H, Hanagasi H, Ertan S, Yilmazer S, Dursun E (2017b) GC and VDR SNPs and vitamin D levels in Parkinson’s disease: the relevance to clinical features. NeuroMolecular Med 19(1):24–40. https://doi.org/10.1007/s12017-016-8415-9 CrossRefGoogle Scholar
- IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) (1982) Nomenclature of vitamin D. Recommendations 1981. Eur J Biochem 124(2):223–227Google Scholar
- Lin YC, Hsieh LC, Kuo MW, Yu J, Kuo HH, Lo WL, Lin RJ, Yu AL, Li WH (2007) Human TRIM71 and its nematode homologue are targets of let-7 microRNA and its zebrafish orthologue is essential for development. Mol Biol Evol 24(11):2525–2534. https://doi.org/10.1093/molbev/msm195 CrossRefPubMedPubMedCentralGoogle Scholar
- Masoumi A, Goldenson B, Ghirmai S, Avagyan H, Zaghi J, Abel K, Zheng X, Espinosa-Jeffrey A, Mahanian M, Liu PT, Hewison M, Mizwickie M, Cashman J, Fiala M (2009) 1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 17(3):703–717CrossRefPubMedPubMedCentralGoogle Scholar
- McKeever PM, Schneider R, Taghdiri F, Weichert A, Multani N, Brown RA, Boxer AL, Karydas A, Miller B, Robertson J, Tartaglia MC (2018) MicroRNA expression levels are altered in the cerebrospinal fluid of patients with young-onset Alzheimer’s disease. Mol Neurobiol 55:8826–8841. https://doi.org/10.1007/s12035-018-1032-x CrossRefPubMedPubMedCentralGoogle Scholar
- Mizwicki MT, Liu G, Fiala M, Magpantay L, Sayre J, Siani A, Mahanian M, Weitzman R, Hayden EY, Rosenthal MJ, Nemere I, Ringman J, Teplow DB (2013) 1alpha,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-beta phagocytosis and inflammation in Alzheimer’s disease patients. J Alzheimers Dis 34(1):155–170. https://doi.org/10.3233/JAD-121735 CrossRefPubMedPubMedCentralGoogle Scholar
- Nolan T, Hands BE, Bustin SA (2006) Quantification of mRNA using real-time RT-PCR. Natureprotocols 1(3):1556–1582Google Scholar
- Price P, Brewer GJ (1998) Serum-free media for neural cell cultures. In: Fedoroff S, Richardson A (eds) Protocols for neural cell culture, 3rd edn. Humana Press, New Jersey, pp 255–264Google Scholar
- Sutherland MK, Somerville MJ, Yoong LK, Bergeron C, Haussler MR, McLachlan DR (1992) Reduction of vitamin D hormone receptor mRNA levels in Alzheimer as compared to Huntington hippocampus: correlation with calbindin-28k mRNA levels. Brain Res Mol Brain Res 13:239–250CrossRefPubMedPubMedCentralGoogle Scholar
- Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, Yoneda Y (2006) Chronic vitamin D(3) treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res 83:1179–1189CrossRefPubMedPubMedCentralGoogle Scholar
- Tiedt S, Prestel M, Malik R, Schieferdecker N, Duering M, Kautzky V, Stoycheva I, Bock J, Northoff BH, Klein M, Dorn F, Krohn K, Teupser D, Liesz A, Plesnila N, Holdt LM, Dichgans M (2017) RNA-Seq identifies circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as potential biomarkers for acute ischemic stroke. Circ Res 121(8):970–980. https://doi.org/10.1161/CIRCRESAHA.117.311572 CrossRefPubMedPubMedCentralGoogle Scholar
- Wang LL, Pan XL, Wang Y, Tang HD, Deng YL, Ren RJ, Xu W, Ma JF, Wang G, Chen SD (2011) A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer’s disease in the Chinese population. Clin Chim Acta 412(3–4):268–270. https://doi.org/10.1016/j.cca.2010.10.015 CrossRefPubMedPubMedCentralGoogle Scholar