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Are microRNAs the Molecular Link Between Metabolic Syndrome and Alzheimer’s Disease?

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in people over 65 years of age. At present, treatment options for AD address only its symptoms, and there are no available treatments for the prevention or delay of the disease process. Several preclinical and epidemiological studies have linked metabolic risk factors such as hypertension, obesity, dyslipidemia, and diabetes to the pathogenesis of AD. However, the molecular mechanisms that underlie this relationship are not fully understood. Considering that less than 1 % of cases of AD are attributable to genetic factors, the identification of new molecular targets linking metabolic risk factors to neuropathological processes is necessary for improving the diagnosis and treatment of AD. The dysregulation of microRNAs (miRNAs), small non-coding RNAs that regulate several biological processes, has been implicated in the development of different pathologies. In this review, we summarize some of the relevant evidence that points to the role of miRNAs in metabolic syndrome (MetS) and AD and propose that miRNAs may be a molecular link in the complex relationship between both diseases.

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References

  1. Thies W, Bleiler L (2013) 2013 Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245. doi:10.1016/j.jalz.2013.02.003

    Article  Google Scholar 

  2. Ballard C, Gauthier S, Corbett A et al (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/S0140-6736(10)61349-9

    Article  PubMed  Google Scholar 

  3. Inestrosa NC, Varela-Nallar L (2014) Wnt signaling in the nervous system and in Alzheimer’s disease. J Mol Cell Biol 6:64–74. doi:10.1093/jmcb/mjt051

    Article  PubMed  Google Scholar 

  4. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi:10.1126/science.1072994

    Article  CAS  PubMed  Google Scholar 

  5. Kanekiyo T, Xu H, Bu G (2014) ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81:740–754. doi:10.1016/j.neuron.2014.01.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De la Monte SM (2014) Type 3 diabetes is sporadic Alzheimer’s disease: mini-review. Eur Neuropsychopharmacol. doi:10.1016/j.euroneuro.2014.06.008

    PubMed  PubMed Central  Google Scholar 

  7. Li Z, Zhang W, Sima AAF (2007) Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56:1817–1824. doi:10.2337/db07-0171

    Article  CAS  PubMed  Google Scholar 

  8. Mehla J, Chauhan BC, Chauhan NB (2014) Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits. J Alzheimers Dis 39:145–162. doi:10.3233/JAD-131238

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Csiszar A, Tucsek Z, Toth P et al (2013) Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer’s disease. Am J Physiol Heart Circ Physiol 305:H1120–H1130. doi:10.1152/ajpheart.00288.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thirumangalakudi L, Prakasam A, Zhang R et al (2008) High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem 106:475–485. doi:10.1111/j.1471-4159.2008.05415.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang L, Dasuri K, Fernandez-Kim S-O et al (2013) Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice. Biochim Biophys Acta 1832:1456–1462. doi:10.1016/j.bbadis.2013.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nelson L, Gard P, Tabet N (2014) Hypertension and inflammation in Alzheimer’s disease: close partners in disease development and progression. J Alzheimers Dis. doi:10.3233/JAD-140024

    Google Scholar 

  13. Solomon A, Kivipelto M, Wolozin B et al (2009) Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28:75–80. doi:10.1159/000231980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Whitmer RA, Gustafson DR, Barrett-Connor E et al (2008) Central obesity and increased risk of dementia more than three decades later. Neurology 71:1057–1064. doi:10.1212/01.wnl.0000306313.89165.ef

    Article  CAS  PubMed  Google Scholar 

  15. Ahtiluoto S, Polvikoski T, Peltonen M et al (2010) Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75:1195–1202. doi:10.1212/WNL.0b013e3181f4d7f8

    Article  CAS  PubMed  Google Scholar 

  16. Thambisetty M, Jeffrey Metter E, Yang A et al (2013) Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol 70:1167–1172. doi:10.1001/jamaneurol.2013.284

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ott A, Stolk RP, van Harskamp F et al (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53:1937–1942

    Article  CAS  PubMed  Google Scholar 

  18. Frisardi V, Solfrizzi V, Seripa D et al (2010) Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res Rev 9:399–417. doi:10.1016/j.arr.2010.04.007

    Article  PubMed  Google Scholar 

  19. Solfrizzi V, Panza F, Colacicco AM et al (2004) Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 63:1882–1891. doi:10.1212/01.WNL.0000144281.38555.E3

    Article  CAS  PubMed  Google Scholar 

  20. Profenno LA, Porsteinsson AP, Faraone SV (2010) Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67:505–512. doi:10.1016/j.biopsych.2009.02.013

    Article  PubMed  Google Scholar 

  21. De la Monte SM, Tong M (2013) Brain metabolic dysfunction at the core of Alzheimer’s disease. Biochem Pharmacol. doi:10.1016/j.bcp.2013.12.012

    PubMed Central  Google Scholar 

  22. Frisardi V, Solfrizzi V, Capurso C et al (2010) Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome? J Alzheimers Dis 21:57–63. doi:10.3233/JAD-2010-100015

    CAS  PubMed  Google Scholar 

  23. Panza F, Solfrizzi V, Logroscino G et al (2012) Current epidemiological approaches to the metabolic-cognitive syndrome. J Alzheimers Dis 30(Suppl 2):S31–S75. doi:10.3233/JAD-2012-111496

    PubMed  Google Scholar 

  24. Roberts RO, Geda YE, Knopman DS, et al (2010) Metabolic syndrome, inflammation, and nonamnestic mild cognitive impairment in older persons: a population-based study. Alzheimer Dis Assoc Disord 24:11–18. doi: 10.1097/WAD.0b013e3181a4485c

  25. Luque-Contreras D, Carvajal K, Toral-Rios D et al (2014) Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer’s disease? Oxidative Med Cell Longev. doi:10.1155/2014/497802

    Google Scholar 

  26. Oskarsson ME, Paulsson JF, Schultz SW et al (2015) In vivo seeding and cross-seeding of localized amyloidosis. Am J Pathol 185:834–846. doi:10.1016/j.ajpath.2014.11.016

    Article  CAS  PubMed  Google Scholar 

  27. Knowles TPJ, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15:384–396. doi:10.1038/nrm3810

    Article  CAS  PubMed  Google Scholar 

  28. Guan J, Zhao HL, Sui Y et al (2009) Histopathological correlations of islet amyloidosis and hyaline arteriosclerosis with amylin gene mutations and apolipoprotein E polymorphisms in Chinese patients with type 2 diabetes. Diabetes 58:A368–A368. doi:10.1097/MPA.0b013e3182965e6e

    Google Scholar 

  29. Ríos JA, Cisternas P, Arrese M et al (2014) Is Alzheimer’s disease related to metabolic syndrome? A Wnt signaling conundrum. Prog Neurobiol. doi:10.1016/j.pneurobio.2014.07.004

    PubMed  Google Scholar 

  30. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. doi:10.1016/S0092-8674(04)00045-5

    Article  CAS  PubMed  Google Scholar 

  31. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233. doi:10.1016/j.cell.2009.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rottiers V, Näär AM (2012) MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol 13:239–250. doi:10.1038/nrm3313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McGregor RA, Choi MS (2011) microRNAs in the regulation of adipogenesis and obesity. Curr Mol Med 11:304–316. doi:10.2174/156652411795677990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mao Y, Mohan R, Zhang S, Tang X (2013) MicroRNAs as pharmacological targets in diabetes. Pharmacol Res 75:37–47. doi:10.1016/j.phrs.2013.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ling S, Nanhwan M, Qian J et al (2013) Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways. J Mol Cell Cardiol 65:127–136. doi:10.1016/j.yjmcc.2013.10.003

    Article  CAS  PubMed  Google Scholar 

  36. Dimmeler S, Nicotera P (2013) MicroRNAs in age-related diseases. EMBO Mol Med 5:180–190. doi:10.1002/emmm.201201986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li Y, Qiu C, Tu J et al (2014) HMDD v2.0: a database for experimentally supported human microRNA and disease associations. Nucleic Acids Res 42:D1070–D1074. doi:10.1093/nar/gkt1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kawamata T, Tomari Y (2010) Making RISC. Trends Biochem Sci 35:368–376. doi:10.1016/j.tibs.2010.03.009

    Article  CAS  PubMed  Google Scholar 

  39. Kawamata T, Yoda M, Tomari Y (2011) Multilayer checkpoints for microRNA authenticity during RISC assembly. EMBO Rep 12:944–949. doi:10.1038/embor.2011.128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kwak PB, Tomari Y (2012) The N domain of Argonaute drives duplex unwinding during RISC assembly. Nat Struct Mol Biol 19:145–151. doi:10.1038/nsmb.2232

    Article  CAS  PubMed  Google Scholar 

  41. Dávalos A, Goedeke L, Smibert P et al (2011) miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A 108:9232–9237. doi:10.1073/pnas.1102281108

    Article  PubMed  PubMed Central  Google Scholar 

  42. Najafi-Shoushtari SH, Kristo F, Li Y et al (2010) MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328:1566–1569. doi:10.1126/science.1189123

    Article  CAS  PubMed  Google Scholar 

  43. Dill H, Linder B, Fehr A, Fischer U (2012) Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. Genes Dev 26:25–30. doi:10.1101/gad.177774.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rokavec M, Li H, Jiang L, Hermeking H (2014) The p53/miR-34 axis in development and disease. J Mol Cell Biol 6:214–230. doi:10.1093/jmcb/mju003

    Article  CAS  PubMed  Google Scholar 

  45. Boominathan L (2010) The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer Metastasis Rev 29:613–639. doi:10.1007/s10555-010-9257-9

    Article  CAS  PubMed  Google Scholar 

  46. Zovoilis A, Agbemenyah HY, Agis-Balboa RC et al (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308. doi:10.1038/emboj.2011.327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hooper C, Meimaridou E, Tavassoli M et al (2007) p53 is upregulated in Alzheimer’s disease and induces tau phosphorylation in HEK293a cells. Neurosci Lett 418:34–37. doi:10.1016/j.neulet.2007.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bialopiotrowicz E, Szybinska A, Kuzniewska B et al (2012) Highly pathogenic Alzheimer’s disease presenilin 1 P117R mutation causes a specific increase in p53 and p21 protein levels and cell cycle dysregulation in human lymphocytes. J Alzheimers Dis 32:397–415. doi:10.3233/JAD-2012-121129

    CAS  PubMed  Google Scholar 

  49. Roe CM, Behrens MI (2013) AD and cancer: epidemiology makes for strange bedfellows. Neurology 81:310–311. doi:10.1212/WNL.0b013e31829c5f16

    Article  PubMed  Google Scholar 

  50. Behrens MI, Silva M, Salech F et al (2012) Inverse susceptibility to oxidative death of lymphocytes obtained from Alzheimer’s patients and skin cancer survivors: increased apoptosis in Alzheimer's and reduced necrosis in cancer. J Gerontol A Biol Sci Med Sci 67:1036–1040. doi:10.1093/gerona/glr258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Driver JA, Beiser A, Au R et al (2012) Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study. BMJ 344, e1442

    Article  PubMed  PubMed Central  Google Scholar 

  52. Demetrius LA, Simon DK (2013) The inverse association of cancer and Alzheimer’s: a bioenergetic mechanism. J R Soc Interface 10:20130006. doi:10.1098/rsif.2013.0006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Musicco M, Adorni F, Di Santo S et al (2013) Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology 81:322–328. doi:10.1212/WNL.0b013e31829c5ec1

    Article  PubMed  Google Scholar 

  54. Castro RE, Ferreira DMS, Afonso MB et al (2013) miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease. J Hepatol 58:119–125. doi:10.1016/j.jhep.2012.08.008

    Article  CAS  PubMed  Google Scholar 

  55. Gregory RI, Yan K-P, Amuthan G et al (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240. doi:10.1038/nature03120

    Article  CAS  PubMed  Google Scholar 

  56. Denli AM, Tops BBJ, Plasterk RH et al (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432:231–235. doi:10.1038/nature03049

    Article  CAS  PubMed  Google Scholar 

  57. Han J, Lee Y, Yeom K-H et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125:887–901. doi:10.1016/j.cell.2006.03.043

    Article  CAS  PubMed  Google Scholar 

  58. Lund E, Güttinger S, Calado A et al (2004) Nuclear export of microRNA precursors. Science 303:95–98. doi:10.1126/science.1090599

    Article  CAS  PubMed  Google Scholar 

  59. Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–3016. doi:10.1101/gad.1158803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Okada C, Yamashita E, Lee SJ et al (2009) A high-resolution structure of the pre-microRNA nuclear export machinery. Science 326:1275–1279. doi:10.1126/science.1178705

    Article  CAS  PubMed  Google Scholar 

  61. Macrae IJ, Zhou K, Li F et al (2006) Structural basis for double-stranded RNA processing by Dicer. Science 311:195–198. doi:10.1126/science.1121638

    Article  CAS  PubMed  Google Scholar 

  62. Bernstein E, Kim SY, Carmell MA et al (2003) Dicer is essential for mouse development. Nat Genet 35:215–217. doi:10.1038/ng1253

    Article  CAS  PubMed  Google Scholar 

  63. Davis TH, Cuellar TL, Koch SM et al (2008) Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 28:4322–4330. doi:10.1523/JNEUROSCI.4815-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cuellar TL, Davis TH, Nelson PT et al (2008) Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc Natl Acad Sci U S A 105:5614–5619. doi:10.1073/pnas.0801689105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kim J, Inoue K, Ishii J et al (2007) A microRNA feedback circuit in midbrain dopamine neurons. Science 317:1220–1224. doi:10.1126/science.1140481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schaefer A, O’Carroll D, Tan CL et al (2007) Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 204:1553–1558. doi:10.1084/jem.20070823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kawase-Koga Y, Low R, Otaegi G et al (2010) RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells. J Cell Sci 123:586–594. doi:10.1242/jcs.059659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hébert SS, Papadopoulou AS, Smith P et al (2010) Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet 19:3959–3969. doi:10.1093/hmg/ddq311

    Article  PubMed  CAS  Google Scholar 

  69. Schneeberger M, Altirriba J, García A et al (2012) Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to pituitary dysfunction, neurodegeneration and development of obesity. Mol Metab 2:74–85. doi:10.1016/j.molmet.2012.10.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Khvorova A, Reynolds A, Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115:209–216. doi:10.1016/S0092-8674(03)00801-8

    Article  CAS  PubMed  Google Scholar 

  71. Chendrimada TP, Gregory RI, Kumaraswamy E et al (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744. doi:10.1038/nature03868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110. doi:10.1038/nrg2936

    Article  CAS  PubMed  Google Scholar 

  73. Vilardo E, Barbato C, Ciotti M et al (2010) MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem 285:18344–18351. doi:10.1074/jbc.M110.112664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524. doi:10.1038/nrm3838

    Article  CAS  PubMed  Google Scholar 

  75. Martinez NJ, Gregory RI (2013) Argonaute2 expression is post-transcriptionally coupled to microRNA abundance. RNA 19:605–612. doi:10.1261/rna.036434.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gibbings D, Mostowy S, Jay F et al (2012) Selective autophagy degrades DICER and AGO2 and regulates miRNA activity. Nat Cell Biol 14:1314–1321. doi:10.1038/ncb2611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ryter SW, Cloonan SM, Choi AMK (2013) Autophagy: a critical regulator of cellular metabolism and homeostasis. Mol Cell 36:7–16. doi:10.1007/s10059-013-0140-8

    Article  CAS  Google Scholar 

  78. Ren SY, Xu X (2014) Role of autophagy in metabolic syndrome-associated heart disease. Biochim Biophys Acta. doi:10.1016/j.bbadis.2014.04.029

    Google Scholar 

  79. Ryter SW, Koo JK, Choi AMK (2014) Molecular regulation of autophagy and its implications for metabolic diseases. Curr Opin Clin Nutr Metab Care 17:329–337. doi:10.1097/MCO.0000000000000068

    Article  CAS  PubMed  Google Scholar 

  80. Wolfe DM, Lee J-H, Kumar A et al (2013) Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci 37:1949–1961. doi:10.1111/ejn.12169

    Article  PubMed  PubMed Central  Google Scholar 

  81. Salminen A, Kaarniranta K, Kauppinen A et al (2013) Impaired autophagy and APP processing in Alzheimer’s disease: the potential role of Beclin 1 interactome. Prog Neurobiol 106–107:33–54. doi:10.1016/j.pneurobio.2013.06.002

    Article  PubMed  CAS  Google Scholar 

  82. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610. doi:10.1038/nrg2843

    CAS  PubMed  Google Scholar 

  83. Fu T, Choi S-E, Kim D-H et al (2012) Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho. Proc Natl Acad Sci U S A 109:16137–16142. doi:10.1073/pnas.1205951109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhou R, Yuan P, Wang Y et al (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34:1395–1405. doi:10.1038/npp.2008.131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee J, Padhye A, Sharma A et al (2010) A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem 285:12604–12611. doi:10.1074/jbc.M109.094524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li X, Khanna A, Li N, Wang E (2011) Circulatory miR34a as an RNA-based, noninvasive biomarker for brain aging. Aging (Albany NY) 3:985–1002

    Article  CAS  Google Scholar 

  87. Godoy JA, Zolezzi JM, Braidy N, Inestrosa NC (2014) Role of Sirt1 during the ageing process: relevance to protection of synapses in the brain. Mol Neurobiol. doi:10.1007/s12035-014-8645-5

    PubMed  Google Scholar 

  88. Codocedo JF, Allard C, Godoy JA et al (2012) SIRT1 regulates dendritic development in hippocampal neurons. PLoS One 7, e47073. doi:10.1371/journal.pone.0047073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Choi S-E, Kemper JK (2013) Regulation of SIRT1 by microRNAs. Mol Cell 36:385–392. doi:10.1007/s10059-013-0297-1

    Article  CAS  Google Scholar 

  90. Lau P, Bossers K, Janky R et al (2013) Alteration of the microRNA network during the progression of Alzheimer’s disease. EMBO Mol Med 5:1613–1634. doi:10.1002/emmm.201201974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schonrock N, Humphreys DT, Preiss T, Götz J (2012) Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-β. J Mol Neurosci 46:324–335. doi:10.1007/s12031-011-9587-2

    Article  CAS  PubMed  Google Scholar 

  92. Ramachandran D, Roy U, Garg S et al (2011) Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin secretion in pancreatic β-islets. FEBS J 278:1167–1174. doi:10.1111/j.1742-4658.2011.08042.x

    Article  CAS  PubMed  Google Scholar 

  93. Barca-Mayo O, De Pietri TD (2014) Convergent microRNA actions coordinate neocortical development. Cell Mol Life Sci 71:2975–2995. doi:10.1007/s00018-014-1576-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schouten M, Aschrafi A, Bielefeld P et al (2013) microRNAs and the regulation of neuronal plasticity under stress conditions. Neuroscience 241:188–205. doi:10.1016/j.neuroscience.2013.02.065

    Article  CAS  PubMed  Google Scholar 

  95. Alberti KGMM, Zimmet P, Shaw J (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062. doi:10.1016/S0140-6736(05)67402-8

    Article  PubMed  Google Scholar 

  96. Cerezo C, Segura J, Praga M, Ruilope LM (2013) Guidelines updates in the treatment of obesity or metabolic syndrome and hypertension. Curr Hypertens Rep 15:196–203. doi:10.1007/s11906-013-0337-4

    Article  PubMed  Google Scholar 

  97. Alberti KGMM, Eckel RH, Grundy SM et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International. Circulation 120:1640–1645. doi:10.1161/CIRCULATIONAHA.109.192644

    Article  CAS  PubMed  Google Scholar 

  98. Goedeke L, Fernández-Hernando C (2014) microRNAs: a connection between cholesterol metabolism and neurodegeneration. Neurobiol Dis 72:3–8. doi: 10.1016/j.nbd.2014.05.034

  99. Gerin I, Clerbaux L-A, Haumont O et al (2010) Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem 285:33652–33661. doi:10.1074/jbc.M110.152090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yvan-Charvet L, Ranalletta M, Wang N et al (2007) Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest 117:3900–3908. doi:10.1172/JCI33372

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Tang C, Oram JF (2009) The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes. Biochim Biophys Acta 1791:563–572. doi:10.1016/j.bbalip.2009.03.011

    Article  CAS  PubMed  Google Scholar 

  102. Rayner KJ, Esau CC, Hussain FN et al (2011) Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478:404–407. doi:10.1038/nature10486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Koldamova R, Fitz NF, Lefterov I (2010) The role of ATP-binding cassette transporter A1 in Alzheimer’s disease and neurodegeneration. Biochim Biophys Acta 1801:824–830. doi:10.1016/j.bbalip.2010.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Alexander R, Lodish H, Sun L (2011) MicroRNAs in adipogenesis and as therapeutic targets for obesity. Expert Opin Ther Targets 15:623–636. doi:10.1517/14728222.2011.561317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xie H, Lim B, Lodish HF (2009) MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 58:1050–1057. doi:10.2337/db08-1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Trajkovski M, Hausser J, Soutschek J et al (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474:649–653. doi:10.1038/nature10112

    Article  CAS  PubMed  Google Scholar 

  107. Angulo P (2007) Obesity and nonalcoholic fatty liver disease. Nutr Rev 65:S57–S63. doi:10.1111/j.1753-4887.2007.tb00329.x

    Article  PubMed  Google Scholar 

  108. Baur JA, Pearson KJ, Price NL et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. doi:10.1038/nature05354

    Article  CAS  PubMed  Google Scholar 

  109. Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10:542–552. doi:10.1038/nrgastro.2013.87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Miyaaki H, Ichikawa T, Kamo Y et al (2013) Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease. Liver Int. doi:10.1111/liv.12429

    Google Scholar 

  111. Yamada H, Suzuki K, Ichino N et al (2013) Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta 424:99–103. doi:10.1016/j.cca.2013.05.021

    Article  CAS  PubMed  Google Scholar 

  112. Pirola CJ, Gianotti TF, Castaño GO, Sookoian S (2013) Circulating microRNA-122 signature in nonalcoholic fatty liver disease and cardiovascular disease: a new endocrine system in metabolic syndrome. Hepatology 57:2545–2547. doi:10.1002/hep.26116

    Article  CAS  PubMed  Google Scholar 

  113. Li J, Ghazwani M, Zhang Y et al (2013) miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol 58:522–528. doi:10.1016/j.jhep.2012.11.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Leavens KF, Birnbaum MJ (2011) Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol 46:200–215. doi:10.3109/10409238.2011.562481

    Article  CAS  PubMed  Google Scholar 

  115. Poy MN, Eliasson L, Krutzfeldt J et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230. doi:10.1038/nature03076

    Article  CAS  PubMed  Google Scholar 

  116. Kim S, Pak Y (2005) Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B fibroblast cells. Biochem Biophys Res Commun 330:88–96. doi:10.1016/j.bbrc.2005.02.130

    Article  CAS  PubMed  Google Scholar 

  117. Ryu HS, Park S-Y, Ma D et al (2011) The induction of microRNA targeting IRS-1 is involved in the development of insulin resistance under conditions of mitochondrial dysfunction in hepatocytes. PLoS One 6, e17343. doi:10.1371/journal.pone.0017343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Pimenta E, Oparil S (2012) Management of hypertension in the elderly. Nat Rev Cardiol 9:286–296. doi:10.1038/nrcardio.2012.27

    Article  CAS  PubMed  Google Scholar 

  119. Coffman TM (2011) Under pressure: the search for the essential mechanisms of hypertension. Nat Med 17:1402–1409. doi:10.1038/nm.2541

    Article  CAS  PubMed  Google Scholar 

  120. Friso S, Carvajal CA, Fardella CE, Olivieri O (2014) Epigenetics and arterial hypertension: the challenge of emerging evidence. Transl Res. doi:10.1016/j.trsl.2014.06.007

    PubMed  Google Scholar 

  121. Feinberg AP (2008) Epigenetics at the epicenter of modern medicine. JAMA 299:1345–1350. doi:10.1001/jama.299.11.1345

    Article  CAS  PubMed  Google Scholar 

  122. Maegdefessel L (2014) The emerging role of microRNAs in cardiovascular disease. J Intern Med. doi:10.1111/joim.12298

    PubMed  Google Scholar 

  123. Kontaraki JE, Marketou ME, Zacharis EA et al (2014) MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. J Am Soc Hypertens 8:368–375. doi:10.1016/j.jash.2014.03.324

    Article  CAS  PubMed  Google Scholar 

  124. Fu X, Guo L, Jiang Z-M et al (2014) An miR-143 promoter variant associated with essential hypertension. Int J Clin Exp Med 7:1813–1817

    PubMed  PubMed Central  Google Scholar 

  125. Nossent AY, Hansen JL, Doggen C et al (2011) SNPs in microRNA binding sites in 3’-UTRs of RAAS genes influence arterial blood pressure and risk of myocardial infarction. Am J Hypertens 24:999–1006. doi:10.1038/ajh.2011.92

    Article  PubMed  CAS  Google Scholar 

  126. Kemp JR, Unal H, Desnoyer R et al (2014) Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 75:25–39. doi:10.1016/j.yjmcc.2014.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Morris R, Mucke L (2006) Alzheimer’s disease: a needle from the haystack. Nature 440:284–285. doi:10.1038/440284a

    Article  CAS  PubMed  Google Scholar 

  128. Hardy J (2006) Has the amyloid cascade hypothesis for Alzheimer’s disease been proved? Curr Alzheimer Res 3:71–73. doi:10.2174/156720506775697098

    Article  CAS  PubMed  Google Scholar 

  129. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739:216–223. doi:10.1016/j.bbadis.2004.08.014

    Article  CAS  PubMed  Google Scholar 

  130. Lukiw WJ (2007) Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 18:297–300. doi:10.1097/WNR.0b013e3280148e8b

    Article  CAS  PubMed  Google Scholar 

  131. Cogswell JP, Ward J, Taylor IA et al (2008) Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14:27–41. doi:10.1016/j.jalz.2008.05.420

    CAS  PubMed  Google Scholar 

  132. Sethi P, Lukiw WJ (2009) Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett 459:100–104. doi:10.1016/j.neulet.2009.04.052

    Article  CAS  PubMed  Google Scholar 

  133. Hébert SS, Horré K, Nicolaï L et al (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105:6415–6420. doi:10.1073/pnas.0710263105

    Article  PubMed  PubMed Central  Google Scholar 

  134. Schonrock N, Ke YD, Humphreys D et al (2010) Neuronal microRNA deregulation in response to Alzheimer’s disease amyloid-beta. PLoS One 5, e11070. doi:10.1371/journal.pone.0011070

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Nunez-Iglesias J, Liu C-C, Morgan TE et al (2010) Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer’s disease cortex reveals altered miRNA regulation. PLoS One 5, e8898. doi:10.1371/journal.pone.0008898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Wang W-X, Huang Q, Hu Y et al (2011) Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121:193–205. doi:10.1007/s00401-010-0756-0

    Article  PubMed  PubMed Central  Google Scholar 

  137. Long JM, Lahiri DK (2011) MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed. Biochem Biophys Res Commun 404:889–895. doi:10.1016/j.bbrc.2010.12.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Fang M, Wang J, Zhang X et al (2012) The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer’s disease. Toxicol Lett 209:94–105. doi:10.1016/j.toxlet.2011.11.032

    Article  CAS  PubMed  Google Scholar 

  139. Wang W-X, Rajeev BW, Stromberg AJ et al (2008) The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28:1213–1223. doi:10.1523/JNEUROSCI.5065-07.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Dickson JR, Kruse C, Montagna DR et al (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127:739–749. doi:10.1111/jnc.12437

    Article  CAS  PubMed  Google Scholar 

  141. Absalon S, Kochanek DM, Raghavan V, Krichevsky AM (2013) MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. J Neurosci 33:14645–14659. doi:10.1523/JNEUROSCI.1327-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Keller A, Leidinger P, Bauer A et al (2011) Toward the blood-borne miRNome of human diseases. Nat Methods 8:841–843. doi:10.1038/nmeth.1682

    Article  CAS  PubMed  Google Scholar 

  143. Schipper HM (2007) Biomarker potential of heme oxygenase-1 in Alzheimer’s disease and mild cognitive impairment. Biomark Med 1:375–385. doi:10.2217/17520363.1.3.375

    Article  CAS  PubMed  Google Scholar 

  144. Bekris LM, Lutz F, Montine TJ et al (2013) MicroRNA in Alzheimer’s disease: an exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers 18:455–466. doi:10.3109/1354750X.2013.814073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Villa C, Ridolfi E, Fenoglio C et al (2013) Expression of the transcription factor Sp1 and its regulatory hsa-miR-29b in peripheral blood mononuclear cells from patients with Alzheimer’s disease. J Alzheimers Dis 35:487–494. doi:10.3233/JAD-122263

    CAS  PubMed  Google Scholar 

  146. Geekiyanage H, Jicha GA, Nelson PT, Chan C (2012) Blood serum miRNA: non-invasive biomarkers for Alzheimer’s disease. Exp Neurol 235:491–496. doi:10.1016/j.expneurol.2011.11.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Leidinger P, Backes C, Deutscher S et al (2013) A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 14:R78. doi:10.1186/gb-2013-14-7-r78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Dorval V, Nelson PT, Hébert SS (2013) Circulating microRNAs in Alzheimer’s disease: the search for novel biomarkers. Front Mol Neurosci 6:24. doi:10.3389/fnmol.2013.00024

    PubMed  PubMed Central  Google Scholar 

  149. Craft S (2005) Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 26(Suppl 1):65–69. doi:10.1016/j.neurobiolaging.2005.08.021

    Article  PubMed  CAS  Google Scholar 

  150. Westermark GT, Westermark P (2013) Islet amyloid polypeptide and diabetes. Curr Protein Pept Sci 14:330–337

    Article  CAS  PubMed  Google Scholar 

  151. Qiu C, Chen G, Cui Q (2012) Towards the understanding of microRNA and environmental factor interactions and their relationships to human diseases. Sci Rep 2:318. doi:10.1038/srep00318

    PubMed  PubMed Central  Google Scholar 

  152. Jéquier E (2002) Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 967:379–388

    Article  PubMed  Google Scholar 

  153. Peiser C, McGregor GP, Lang RE (2000) Leptin receptor expression and suppressor of cytokine signaling transcript levels in high-fat-fed rats. Life Sci 67:2971–81

  154. Zlokovic BV, Jovanovic S, Miao W et al (2000) Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology 141:1434–41. doi:10.1210/endo.141.4.7435

  155. Morash B, Li A, Murphy PR et al (1999) Leptin gene expression in the brain and pituitary gland. Endocrinology 140:5995–8. doi:10.1210/endo.140.12.7288

  156. Wiesner G, Vaz M, Collier G et al (1999) Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 84:2270–4. doi:10.1210/jcem.84.7.5854

  157. Ur E, Wilkinson DA, Morash BA, Wilkinson M (2002) Leptin immunoreactivity is localized to neurons in rat brain. Neuroendocrinology 75:264–72

  158. Grill HJ, Schwartz MW, Kaplan JM et al (2002) Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143:239–46. doi:10.1210/endo.143.1.8589

  159. Guan XM, Hess JF, Yu H et al (1997) Differential expression of mRNA for leptin receptor isoforms in the rat brain. Mol Cell Endocrinol 133:1–7

  160. Huang XF, Koutcherov I, Lin S et al (1996) Localization of leptin receptor mRNA expression in mouse brain. Neuroreport 7:2635–8

  161. Shioda S, Funahashi H, Nakajo S et al (1998) Immunohistochemical localization of leptin receptor in the rat brain. Neurosci Lett 243:41–4

  162. Bouret SG (2010) Neurodevelopmental actions of leptin. Brain Res 1350:2–9. doi:10.1016/j.brainres.2010.04.011

  163. Paz-Filho G, Wong M-L, Licinio J (2010) The procognitive effects of leptin in the brain and their clinical implications. Int J Clin Pract 64:1808–12. doi:10.1111/j.1742-1241.2010.02536.x

  164. Xu G, Ji C, Shi C et al (2013) Modulation of hsa-miR-26b levels following adipokine stimulation. Mol Biol Rep 40:3577–3582. doi:10.1007/s11033-012-2431-0

    Article  CAS  PubMed  Google Scholar 

  165. Arnoldussen IAC, Kiliaan AJ, Gustafson DR (2014) Obesity and dementia: adipokines interact with the brain. Eur Neuropsychopharmacol 1–18. doi: 10.1016/j.euroneuro.2014.03.002

  166. Sergi G, De Rui M, Coin A et al (2013) Weight loss and Alzheimer’s disease: temporal and aetiologic connections. Proc Nutr Soc 72:160–165. doi:10.1017/S0029665112002753

    Article  PubMed  Google Scholar 

  167. Liu QY, Chang MNV, Lei JX et al (2014) Identification of microRNAs involved in Alzheimer’s progression using a rabbit model of the disease. Am J Neurodegener Dis 3:33–44

    PubMed  PubMed Central  Google Scholar 

  168. Marwarha G, Dasari B, Prasanthi JRP et al (2010) Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices. J Alzheimers Dis 19:1007–1019. doi:10.3233/JAD-2010-1298

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Schreurs BG (2013) Cholesterol and copper affect learning and memory in the rabbit. Int J Alzheimers Dis 2013:518780. doi:10.1155/2013/518780

    PubMed  PubMed Central  Google Scholar 

  170. Woodruff-Pak DS, Agelan A, Del Valle L (2007) A rabbit model of Alzheimer’s disease: valid at neuropathological, cognitive, and therapeutic levels. J Alzheimers Dis 11:371–383

    CAS  PubMed  Google Scholar 

  171. Sparks DL (2008) The early and ongoing experience with the cholesterol-fed rabbit as a model of Alzheimer’s disease: the old, the new and the pilot. J Alzheimers Dis 15:641–656

    CAS  PubMed  Google Scholar 

  172. Ghribi O (2008) Potential mechanisms linking cholesterol to Alzheimer’s disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle. J Alzheimers Dis 15:673–684

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Ghribi O, Larsen B, Schrag M, Herman MM (2006) High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exp Neurol 200:460–467. doi:10.1016/j.expneurol.2006.03.019

    Article  CAS  PubMed  Google Scholar 

  174. Ghribi O, Golovko MY, Larsen B et al (2006) Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem 99:438–449. doi:10.1111/j.1471-4159.2006.04079.x

    Article  CAS  PubMed  Google Scholar 

  175. Dhar M, Zhu M, Impey S et al (2014) Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP. Mol Endocrinol 28:1073–1087. doi:10.1210/me.2013-1332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Cogswell JP, Ward J, Taylor IA et al (2008) Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14:27–41

    CAS  PubMed  Google Scholar 

  177. Wyman SK, Knouf EC, Parkin RK et al (2011) Post-transcriptional generation of miRNA variants by multiple nucleotidyl transferases contributes to miRNA transcriptome complexity. Genome Res 21:1450–1461. doi:10.1101/gr.118059.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wong H-KA, Veremeyko T, Patel N et al (2013) De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer’s disease. Hum Mol Genet 22:3077–3092. doi:10.1093/hmg/ddt164

    Article  CAS  PubMed  Google Scholar 

  179. Wayman GA, Davare M, Ando H et al (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A 105:9093–9098. doi:10.1073/pnas.0803072105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Crépin D, Benomar Y, Riffault L et al (2014) The over-expression of miR-200a in the hypothalamus of ob/ob mice is linked to leptin and insulin signaling impairment. Mol Cell Endocrinol 384:1–11. doi:10.1016/j.mce.2013.12.016

    Article  PubMed  CAS  Google Scholar 

  181. Ding Y, Tian M, Liu J et al (2012) Expression profile of miRNAs in APP swe/PSΔE9 transgenic mice. Nan Fang Yi Ke Da Xue Xue Bao 32:1280–1283

    CAS  PubMed  Google Scholar 

  182. Benoit C, Ould-Hamouda H, Crepin D et al (2013) Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs. J Endocrinol 218:35–47. doi:10.1530/JOE-12-0561

    Article  CAS  PubMed  Google Scholar 

  183. Sangiao-Alvarellos S, Pena-Bello L, Manfredi-Lozano M et al (2014) Perturbation of hypothalamic microRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance. Endocrinology 155:1838–1850. doi:10.1210/en.2013-1770

    Article  PubMed  CAS  Google Scholar 

  184. Callen DJ, Black SE, Gao F et al (2001) Beyond the hippocampus: MRI volumetry confirms widespread limbic atrophy in AD. Neurology 57:1669–1674

    Article  CAS  PubMed  Google Scholar 

  185. McDuff T, Sumi SM (1985) Subcortical degeneration in Alzheimer’s disease. Neurology 35:123–126

    Article  CAS  PubMed  Google Scholar 

  186. Saper CB, German DC (1987) Hypothalamic pathology in Alzheimer’s disease. Neurosci Lett 74:364–370

    Article  CAS  PubMed  Google Scholar 

  187. Geekiyanage H, Chan C (2011) MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer’s disease. J Neurosci 31:14820–14830. doi:10.1523/JNEUROSCI.3883-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Lee SJ, Liyanage U, Bickel PE et al (1998) A detergent-insoluble membrane compartment contains A beta in vivo. Nat Med 4:730–734. doi:10.1038/nm0698-730

    Article  CAS  PubMed  Google Scholar 

  189. Vetrivel KS, Cheng H, Kim S-H et al (2005) Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem 280:25892–25900. doi:10.1074/jbc.M503570200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Uranga RM, Bruce-Keller AJ, Morrison CD et al (2010) Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 114:344–361. doi:10.1111/j.1471-4159.2010.06803.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Singh B, Parsaik AK, Mielke MM et al (2013) Association of Mediterranean diet with mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. doi:10.3233/JAD-130830

    Google Scholar 

  192. Khanna A, Muthusamy S, Liang R et al (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging (Albany NY) 3:223–236

    Article  CAS  Google Scholar 

  193. Wang X, Liu P, Zhu H et al (2009) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80:268–273. doi:10.1016/j.brainresbull.2009.08.006

    Article  CAS  PubMed  Google Scholar 

  194. Bowes A, Dawson A, Jepson R, McCabe L (2013) Physical activity for people with dementia: a scoping study. BMC Geriatr 13:129. doi:10.1186/1471-2318-13-129

    Article  PubMed  PubMed Central  Google Scholar 

  195. Maesako M, Uemura K, Kubota M et al (2012) Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice. J Biol Chem 287:23024–23033. doi:10.1074/jbc.M112.367011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Zacharewicz E, Lamon S, Russell AP (2013) MicroRNAs in skeletal muscle and their regulation with exercise, ageing, and disease. Front Physiol 4:266. doi:10.3389/fphys.2013.00266

    Article  PubMed  PubMed Central  Google Scholar 

  197. Mojtahedi S, Kordi MR, Hosseini SE et al (2012) Effect of treadmill running on the expression of genes that are involved in neuronal differentiation in the hippocampus of adult male rats. Cell Biol Int. doi:10.1002/cbin.10022

    Google Scholar 

  198. Smith P, Al Hashimi A, Girard J et al (2011) In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs. J Neurochem 116:240–247. doi:10.1111/j.1471-4159.2010.07097.x

    Article  CAS  PubMed  Google Scholar 

  199. Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S et al (2014) Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise. Front Aging Neurosci 6:51. doi:10.3389/fnagi.2014.00051

    PubMed  PubMed Central  Google Scholar 

  200. Elfving B, Christensen T, Ratner C et al (2013) Transient activation of mTOR following forced treadmill exercise in rats. Synapse 67:620–625. doi:10.1002/syn.21668

    Article  CAS  PubMed  Google Scholar 

  201. Bruel-Jungerman E, Veyrac A, Dufour F et al (2009) Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS One 4, e7901. doi:10.1371/journal.pone.0007901

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Muller AP, Gnoatto J, Moreira JD et al (2011) Exercise increases insulin signaling in the hippocampus: physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice. Hippocampus 21:1082–1092. doi:10.1002/hipo.20822

    Article  CAS  PubMed  Google Scholar 

  203. Jick H, Zornberg GL, Jick SS et al (2000) Statins and the risk of dementia. Lancet 356:1627–1631. doi:10.1097/00006254-200104000-00019

    Article  CAS  PubMed  Google Scholar 

  204. Kandiah N, Feldman HH (2009) Therapeutic potential of statins in Alzheimer’s disease. J Neurol Sci 283:230–234. doi:10.1016/j.jns.2009.02.352

    Article  CAS  PubMed  Google Scholar 

  205. Kurata T, Miyazaki K, Kozuki M et al (2011) Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Res 1371:161–170. doi:10.1016/j.brainres.2010.11.067

    Article  CAS  PubMed  Google Scholar 

  206. Murphy MP, Morales J, Beckett TL et al (2010) Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs. J Alzheimers Dis 22:135–150. doi:10.3233/JAD-2010-100639

    CAS  PubMed  Google Scholar 

  207. Barone E, Di Domenico F, Butterfield DA (2013) Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol. doi:10.1016/j.bcp.2013.10.030

    PubMed  PubMed Central  Google Scholar 

  208. Allen RM, Marquart TJ, Albert CJ et al (2012) miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity. EMBO Mol Med 4:882–895. doi:10.1002/emmm.201201228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Takwi AAL, Li Y, Becker Buscaglia LE et al (2012) A statin-regulated microRNA represses human c-Myc expression and function. EMBO Mol Med 4:896–909. doi:10.1002/emmm.201101045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Guillot F, Misslin P, Lemaire M (1993) Comparison of fluvastatin and lovastatin blood–brain barrier transfer using in vitro and in vivo methods. J Cardiovasc Pharmacol 21:339–346. doi:10.1097/00005344-199302000-00022

    Article  CAS  PubMed  Google Scholar 

  211. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C et al (2012) Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205. Cell Cycle 11:1235–1246. doi:10.4161/cc.11.6.19665

    Article  PubMed  CAS  Google Scholar 

  212. Wang Y, Dai W, Chu X et al (2013) Metformin inhibits lung cancer cells proliferation through repressing microRNA-222. Biotechnol Lett 35:2013–2019. doi:10.1007/s10529-013-1309-0

    Article  CAS  PubMed  Google Scholar 

  213. Li W, Yuan Y, Huang L et al (2012) Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells. Diabetes Res Clin Pract 96:187–195. doi:10.1016/j.diabres.2011.12.028

    Article  CAS  PubMed  Google Scholar 

  214. Blandino G, Valerio M, Cioce M et al (2012) Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun 3:865. doi:10.1038/ncomms1859

    Article  PubMed  CAS  Google Scholar 

  215. Łabuzek K, Suchy D, Gabryel B et al (2010) Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 62:956–965. doi:10.1016/S1734-1140(10)70357-1

    Article  PubMed  Google Scholar 

  216. Moore EM, Mander AG, Ames D et al (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36:2981–2987. doi:10.2337/dc13-0229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Li J, Deng J, Sheng W, Zuo Z (2012) Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav 101:564–574. doi:10.1016/j.pbb.2012.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Imfeld P, Bodmer M, Jick SS, Meier CR (2012) Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case–control study. J Am Geriatr Soc 60:916–921. doi:10.1111/j.1532-5415.2012.03916.x

    Article  PubMed  Google Scholar 

  219. Kurinami H, Shimamura M, Sato N et al (2013) Do angiotensin receptor blockers protect against Alzheimer’s disease? Drugs Aging 30:367–372. doi:10.1007/s40266-013-0071-2

    Article  CAS  PubMed  Google Scholar 

  220. Michel MC, Foster C, Brunner HR, Liu L (2013) A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev 65:809–848. doi:10.1124/pr.112.007278

    Article  PubMed  CAS  Google Scholar 

  221. Fellmann L, Nascimento AR, Tibiriça E, Bousquet P (2013) Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther 137:331–340. doi:10.1016/j.pharmthera.2012.11.004

    Article  CAS  PubMed  Google Scholar 

  222. Alzoubi KH, Aleisa AM, Alkadhi KA (2005) Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in obese Zucker rats: role of calcineurin and phosphorylated CaMKII. J Mol Neurosci 27:337–346. doi:10.1385/JMN:27:3:337

    Article  CAS  PubMed  Google Scholar 

  223. Gerges NZ, Aleisa AM, Alkadhi KA (2003) Impaired long-term potentiation in obese Zucker rats: possible involvement of presynaptic mechanism. Neuroscience 120:535–539. doi:10.1016/S0306-4522(03)00297-5

    Article  CAS  PubMed  Google Scholar 

  224. Kamal A, Ramakers GMJ, Gispen WH et al (2013) Hyperinsulinemia in rats causes impairment of spatial memory and learning with defects in hippocampal synaptic plasticity by involvement of postsynaptic mechanisms. Exp Brain Res 226:45–51. doi:10.1007/s00221-013-3409-4

    Article  PubMed  Google Scholar 

  225. Knight DS, Mahajan DK, Qiao X (2001) Dietary fat up-regulates the apolipoprotein E mRNA level in the Zucker lean rat brain. Neuroreport 12:3111–3115. doi:10.1097/00001756-200110080-00026

    Article  CAS  PubMed  Google Scholar 

  226. Doherty GH, Beccano-Kelly D, Du Yan S et al (2013) Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid. Neurobiol Aging 34:226–237. doi:10.1016/j.neurobiolaging.2012.08.003

    Article  CAS  PubMed  Google Scholar 

  227. Talaei F, Van Praag VM, Shishavan MH et al (2014) Increased protein aggregation in Zucker diabetic fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide. BMC Cell Biol 15:1. doi:10.1186/1471-2121-15-1

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants PFB 12/2007 from the Basal Centre for Excellence in Science and Technology, FONDECYT 1120156, MIFAB Foundation, and Fundación Ciencia y Vida to NCI and pre-doctoral fellowships from CONICYT to JAR and JFC. Graphic work was carried out by illustrative science (www.illustrative-science.com).

Statement of Author Contributions

NCI and JFC conceived the review concept. JFC and JAR carried out the literature search. JFC designed the figures and table. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Authors and Affiliations

  1. Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular, Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Juan F. Codocedo, Juvenal A. Ríos, Juan A. Godoy & Nibaldo C. Inestrosa

  2. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nibaldo C. Inestrosa

  3. Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile

    Nibaldo C. Inestrosa

  4. Centro de excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    Nibaldo C. Inestrosa

  5. CARE Biomedical Research Center, Pontificia Universidad Católica de Chile, Av. Alameda 340, Santiago, Chile

    Nibaldo C. Inestrosa

Authors
  1. Juan F. Codocedo
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  2. Juvenal A. Ríos
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  3. Juan A. Godoy
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  4. Nibaldo C. Inestrosa
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Correspondence to Nibaldo C. Inestrosa.

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Codocedo, J.F., Ríos, J.A., Godoy, J.A. et al. Are microRNAs the Molecular Link Between Metabolic Syndrome and Alzheimer’s Disease?. Mol Neurobiol 53, 2320–2338 (2016). https://doi.org/10.1007/s12035-015-9201-7

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