Inhibition of microRNA-155 Alleviates Cognitive Impairment in Alzheimer’s Disease and Involvement of Neuroinflammation

Author(s): Dandan Liu, Dandan Zhao, Yingkai Zhao, Yan Wang, Yong Zhao*, Chengfei Wen*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 6 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Background: Neuroinflammation has important effects on cognitive functions in the pathophysiological process of Alzheimer’s Disease (AD). In the current report, we determined the effects of microRNA-155 (miR-155) on the levels of IL-1β, IL-6 and TNF-α, and their respective receptors in the hippocampus using a rat model of AD.

Methods: Real-time RT-PCR, ELISA and western blot analysis were used to examine the miR-155, PICs and PIC receptors. The Morris water maze and spatial working memory tests were used to assess cognitive functions.

Results: miR-155 was increased in the hippocampus of AD rats, accompanied by amplification of IL-1β, IL-6 and TNF-α. Intracerebroventricular infusion of miR-155 inhibitor, but not its scramble attenuated the increases of IL-1β, IL-6 and TNF-α and upregulation of their receptors. MiR-155 inhibitor also attenuated upregulation of apoptotic Caspase-3 in the hippocampus of AD rats. Notably, inhibition of miR- 155 or PIC receptors largely recovered the impaired learning performance in AD rat.

Conclusion: We showed the critical role of miR-155 in regulating the memory impairment in AD rats likely via engagement of neuroinflammatory mechanisms, suggesting that miR-155 and its signaling molecules may present prospects in preventing and/or improving the development of the impaired cognitive functions in AD.

Keywords: miroRNA-155, pro-inflammatory cytokines, Caspase-3, hippocampus, Alzheimer's disease, neuroinflammation.

Burns A, Iliffe S. Alzheimer’s disease. BMJ 338: b158.2009.
Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 362: 329-44.2010.
Piton M, Hirtz C, Desmetz C, Milhau J, Lajoix AD, Bennys K, et al. Alzheimer’s Disease: advances in drug development. J Alzheimers Dis 65: 3-13.2018.
Marttinen M, Takalo M, Natunen T, Wittrahm R, Gabbouj S, Kemppainen S, et al. Molecular mechanisms of synaptotoxicity and neuroinflammation in Alzheimer’s disease. Front Neurosci 12: 963.2018.
Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog Neurobiol 174: 53-89.2019.
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1a0061892011.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 136: 215-33.2009.
Sayed D, Abdellatif M. MicroRNAs in development and disease. Physiol Rev 91: 827-87.2011.
Eacker SM, Dawson TM, Dawson VL. Understanding microRNAs in neurodegeneration. Nat Rev Neurosci 10: 837-41.2009.
Farazi TA, Spitzer JI, Morozov P, Tuschl T. miRNAs in human cancer. J Pathol 223: 102-15.2011.
Han M, Toli J, Abdellatif M. MicroRNAs in the cardiovascular system. Curr Opin Cardiol 26: 181-9.2011.
Gambari R, Fabbri E, Borgatti M, Lampronti I, Finotti A, Brognara E, et al. Targeting microRNAs involved in human diseases: a novel approach for modification of gene expression and drug development. Biochem Pharmacol 82: 1416-29.2011.
Hill JM, Pogue AI, Lukiw WJ. Pathogenic microRNAs common to brain and retinal degeneration; recent observations in alzheimer’s disease and age-related macular degeneration. Front Neurol 6: 232.2015.
Martinez B, Peplow PV. MicroRNAs as diagnostic and therapeutic tools for Alzheimer’s disease: advances and limitations. Neural Regen Res 14: 242-55.2019.
Arena A, Iyer AM, Milenkovic I, Kovacs GG, Ferrer I, Perluigi M, et al. Developmental expression and dysregulation of mir-146a and mir-155 in Down’s syndrome and mouse models of down’s syndrome and Alzheimer’s disease. Curr Alzheimer Res 14: 1305-17.2017.
Gupta P, Bhattacharjee S, Sharma AR, Sharma G, Lee SS, Chakraborty C. miRNAs in Alzheimer disease - a therapeutic perspective. Curr Alzheimer Res 14: 1198-206.2017.
Lau P, Bossers K, Janky R, Salta E, Frigerio CS, Barbash S, et al. Alteration of the microRNA network during the progression of Alzheimer’s disease. EMBO Mol Med 5: 1613-34.2013.
Long JM, Maloney B. Novel upregulation of amyloid-beta precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region implications in Alzheimer's disease 24: 345-63.2019.
Long JM, Maloney B. Novel upregulation of amyloid-beta precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease. Mol Psychiatry 24: 345-63.2019.
Long JM, Ray B, Lahiri DK. MicroRNA-153 physiologically inhibits expression of amyloid-beta precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. J Biol Chem 287: 31298-310.2012.
Long JM, Ray B, Lahiri DK. MicroRNA-339-5p down-regulates protein expression of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem 289: 5184-98.2014.
Pereira PA, Tomas JF, Queiroz JA, Figueiras AR, Sousa F. Recombinant pre-miR-29b for Alzheimer’s disease therapeutics. Sci Rep 6: 19946.2016.
Shaltiel G, Hanan M, Wolf Y, Barbash S, Kovalev E, Shoham S, et al. Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target. Brain Struct Funct 218: 59-72.2013.
Zhao J, Chen C, Guo M, Tao Y, Cui P, Zhou Y, et al. MicroRNA-7 deficiency ameliorates the pathologies of acute lung injury through Elevating KLF4. Front Immunol 7: 389.2016.
Kumar S, Reddy PH. Are circulating microRNAs peripheral biomarkers for Alzheimer’s disease? Biochim Biophys Acta 1862: 1617-27.2016.
Yilmaz SG, Erdal ME, Ozge AA, Sungur MA. Can peripheral Microrna expression data serve as epigenomic (Upstream) biomarkers of alzheimer’s disease? OMICS 20: 456-61.2016.
Dehghani R, Rahmani F, Rezaei N. MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms. Rev Neurosci 29: 161-82.2018.
Wang X, Tan L, Lu Y, Peng J, Zhu Y, Zhang Y, et al. MicroRNA-138 promotes tau phosphorylation by targeting retinoic acid receptor alpha. FEBS Lett 589: 726-9.2015.
Zhao J, Yue D, Zhou Y, Jia L, Wang H, Guo M, et al. The Role of MicroRNAs in Abeta Deposition and Tau Phosphorylation in Alzheimer’s Disease. Front Neurol 8: 342.2017.
Schonrock N, Humphreys DT, Preiss T, Gotz J. Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-beta. J Mol Neurosci 46: 324-35.2012.
Bekris LM, Leverenz JB. The biomarker and therapeutic potential of miRNA in Alzheimer’s disease. Neurodegener Dis Manag 5: 61-74.2015.
Wang X, Liu P, Zhu H, Xu Y, Ma C, Dai X, et al. miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80: 268-73. (2009)
Smith P, Al Hashimi A, Girard J, Delay C, Hebert SS. In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs. J Neurochem 116: 240-7. (2011)
Calame K. MicroRNA-155 function in B Cells. Immunity 27: 825-7. (2007)
Elton TS, Selemon H, Elton SM, Parinandi NL. Regulation of the MIR155 host gene in physiological and pathological processes. Gene 532: 1-12. (2013)
Faraoni I, Antonetti FR, Cardone J, Bonmassar E. miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792: 497-505. (2009)
O’Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol 30: 295-312. (2012)
Sonkoly E, Janson P, Majuri ML, Savinko T, Fyhrquist N, Eidsmo L, et al. MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4 J Allergy Clin Immunol 126: 581-589. : e581-520. (2010)
Moore CS, Rao VT, Durafourt BA, Bedell BJ, Ludwin SK, Bar-Or A, et al. miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann Neurol 74: 709-20. (2013)
Wang X, Li GJ, Hu HX, Ma C, Ma DH, Liu XL, et al. Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats. Transl Neurosci 7: 151-7. (2016)
Swanson LW. Brain maps: structure of the rat brain, 2nd Elsevier, New York,. (1998)
Lecanu L, Papadopoulos V. Modeling Alzheimer’s disease with non-transgenic rat models. Alzheimers Res Ther 5: 17. (2013)
Lecanu L, Greeson J, Papadopoulos V. Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain. Pharmacology 76: 19-33. (2006)
Nakamura S, Murayama N, Noshita T, Annoura H, Ohno T. Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide. Brain Res 912: 128-36. (2001)
Sochocka M, Koutsouraki ES, Gasiorowski K, Leszek J. Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer’s disease: a new approach to therapy. CNS Neurol Disord Drug Targets 12: 870-81. (2013)
Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 62: 90-101. (2013)
Butterfield DA, Swomley AM, Sultana R. Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19: 823-35. (2013)
Su F, Bai F, Zhang Z. Inflammatory cytokines and alzheimer’s disease: a review from the perspective of genetic polymorphisms. Neurosci Bull 32: 469-80. (2016)
Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300(Pt 2): 281-90. (1994)
Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58: 573-81. (1989)
MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal 14: 477-92. (2002)
Probert L. TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302: 2-22. (2015)
Sinha A, Tamboli RS, Seth B, et al. Neuroprotective role of novel triazine derivatives by activating wnt/beta catenin signaling pathway in rodent models of Alzheimer’s disease. Mol Neurobiol 52: 638-52. (2015)
Yun N, Lee YM, Kim C, Shibayama H, Tanimura A, Hamanaka Y, et al. Anamorsin, a novel caspase-3 substrate in neurodegeneration. J Biol Chem 289: 22183-95. (2014)
Salvesen GS. Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 9: 3-5. (2002)
Walters J, Pop C, Scott FL, Drag M, Swartz P, Mattos C, et al. A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis. Biochem J 424: 335-45. (2009)
Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725-31. (2003)
Lai J, Hu M, Wang H, Hu M, Long Y, Miao MX, et al. Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Abeta1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice. Neuropharmacology 79: 707-14. (2014)
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63: 287-303. (2009)
Sun JH, Yu JT, Tan L. The role of cholesterol metabolism in Alzheimer’s disease. Mol Neurobiol 51: 947-65. (2015)
Dumortier O, Hinault C, Van Obberghen E. MicroRNAs and metabolism crosstalk in energy homeostasis. Cell Metab 18: 312-24. (2013)
Goedeke L, Aranda JF, Fernandez-Hernando C. microRNA regulation of lipoprotein metabolism. Curr Opin Lipidol 25: 282-8. (2014)
He X, Huang Y, Li B, Gong CX, Schuchman EH. Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31: 398-408. (2010)
Patil S, Melrose J, Chan C. Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons. Eur J Neurosci 26: 2131-41. (2007)
Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9: 139-50. (2008)
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA 101: 2070-5. (2004)
Yoon H, Flores LF, Kim J. MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer’s disease. Biochim Biophys Acta 1861: 2139-47. (2016)
Geekiyanage H, Chan C. MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer’s disease. J Neurosci 31: 14820-30. (2011)
de Aguiar Vallim TQ, Tarling EJ, Kim T, Civelek M, Baldan A, Esau C, et al. MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ Res 112: 1602-12. (2013)
Kim J, Yoon H, Ramirez CM, Lee SM, Hoe HS, Fernandez-Hernando C, et al. MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression. Exp Neurol 235: 476-83. (2012)
Ramirez CM, Davalos A, Goedeke L, Salerno AG, Warrier N, Cirera-Salinas D, et al. MicroRNA-758 regulates cholesterol efflux through posttranscriptional repression of ATP-binding cassette transporter A1. Arterioscler Thromb Vasc Biol 31: 2707-14. (2011)
Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328: 1570-3. (2010)
Kim J, Yoon H, Horie T, et al. microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain. J Neurosci 35: 14717-26. (2015)
Fratiglioni L, Grut M, Forsell Y, Viitanen M, Grafstrom M, Holmen K, et al. Prevalence of Alzheimer’s disease and other dementias in an elderly urban population: relationship with age, sex, and education. Neurology 41: 1886-92. (1991)
Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer’s disease. Curr Opin Psychiatry 31: 133-9. (2018)

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [473 - 482]
Pages: 10
DOI: 10.2174/1567205016666190503145207
Price: $65

Article Metrics

PDF: 50