A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect

Journal of Translational Medicine

Martin Hofmann-Apitius¹  Erfan Younesi¹ 

[1] Bonn-Aachen International Center for Information Technology, University of Bonn, Bonn, Germany

关键词: Off-target effect;    Translational validation;    Network model;    Dementia;    Hormone;   

Others  :  827040
DOI  :  10.1186/1479-5876-11-177

 received in 2013-04-05, accepted in 2013-07-03,  发布年份 2013

【 摘 要 】

Background

While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued.

Methods

Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on ‘serendipitous off-target effects’.

Results

Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia.

Conclusions

The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer’s disease.

【 授权许可】

   
2013 Younesi and Hofmann-Apitius; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Brooks DJ: Imaging amyloid in Parkinson’s disease dementia and dementia with Lewy bodies with positron emission tomography. Mov Disord 2009, 24(Suppl 2):S742-S747.
• [2]Vanmechelen E, Vanderstichele H, Hulstaert F, Andreasen N, Minthon L, Winbald B, Davidsson P, Blennow K: Cerebrospinal fluid τ and β-amyloid(1–42) in dementia disorders. Mech Ageing Dev 2001, 122:2005-2011.
• [3]Ross CA, Poirier MA: Protein aggregation and neurodegenerative disease. Nat Med 2004, 10:S10-S17.
• [4]Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K, Rissman RA, Singru PS, Nilsson KP, Simon R, Schubert D, Eisenberg D, Rivier J, Sawchenko P, Vale W, Riek R: Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 2009, 325:328-332.
• [5]Gibbs RB: Estrogen therapy and cognition: a review of the cholinergic hypothesis. Endocr Rev 2010, 31:224-253.
• [6]Artero S, Ancelin ML, Portet F, Dupuy A, Berr C, Dartigues JF, Tzourio C, Rouaud O, Poncet M, Pasquier F, Auriacombe S, Touchon J, Ritchie K: Risk profiles for mild cognitive impairment and progression to dementia are gender specific. J Neurol Neurosurg Psychiatry 2008, 79:979-984.
• [7]Ravaglia G, Forti P, Maioli F, Bastagli L, Montesi F, Pisacane N, Chiappelli M, Licastro F, Patterson C: Endogenous sex hormones as risk factors for dementia in elderly men and women. J Gerontol A Biol Sci Med Sci 2007, 62:1035-1041.
• [8]Jorm AF, Jolley D: The incidence of dementia, a meta analysis. Neurology 1998, 51:728-733.
• [9]Paganini-Hill A, Henderson V: Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 1996, 156:2213-2217.
• [10]Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R: Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996, 348:429-432.
• [11]Zandi P, Carlson M, Plassman B, Welsh-Bohmer K, Mayer L, Steffens D, Breitner J: Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA-J Am Med Assoc 2002, 288:2123-2129.
• [12]Espeland M, Rapp S, Shumaker S, Brunner R, Manson J, Sherwin B, Hsia J, Margolis K, Hogan P, Wallace R, Dailey M, Freeman R, Hays J: Conjugated equine estrogens and global cognitive function in postmenopausal women. JAMA-J Am Med Assoc 2004, 291:2959-2968.
• [13]Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women’s health initiative memory study: a randomized controlled trial. JAMA-J Am Med Assoc 2003, 289:2651-2662.
• [14]Ryan J, Carriere I, Scali J, Dartigues JF, Tzourio C, Poncet M, Ritchie K, Ancelin ML: Characteristics of hormone therapy, cognitive function, and dementia. Neurology 2009, 73:1729-1737.
• [15]Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S: Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA-J Am Med Assoc 2009, 302:2565-2572.
• [16]Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhou X, Greco SJ, Sarkar S: Leptin: a novel therapeutic strategy for alzheimer’s disease. J Alzheimers Dis 2009, 16:731-740.
• [17]Maurizi CP: Loss of intraventricular fluid melatonin can explain the neuropathology of Alzheimer’s disease. Med Hypotheses 1997, 49:153-158.
• [18]Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF: Decreased melatonin levels in post-mortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab 1999, 84:323-327.
• [19]Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M: Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry 1999, 45:417-421.
• [20]Atsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke-Ikbal I, Wilson GA, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E: Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 2003, 85:1101-1108.
• [21]Breteler MM, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Mortimer JA, Rocca WA, Shalat SL, Soininen H, Hofman A: Medical history and the risk of Alzheimer’s disease: a collaborative re-analysis of case–control studies. Int J Epidemiol 1991, 20(Suppl 2):S36-S42.
• [22]Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST: Association between dementia and elevated TSH: a community-based study. Biol Psychiatry 1996, 40:714-725.
• [23]Fu AL, Zhou CY, Chen X: Thyroid hormone prevents cognitive deficit in a mouse model of Alzheimer’s disease. Neuropharmacology 2010, 58:722-729.
• [24]May C, Rapoport SI, Tomai TP, Chrousos GP, Gold PW: Cerebral spinal fluid concentrations of corticotropin-releasing hormone (CRH) and corticotropin (ACTH) are reduced in patients with Alzheimer’s disease. Neurology 1987, 37:535-538.
• [25]Pomara N, Singh RR, Deptula D, LeWitt PA, Bissette G, Stanley M, Nemeroff CB: CSF corticotropin-releasing factor (CRH) in Alzheimer’s disease. Its relationship to severity of dementia and monoamine metabolites. Biol Psychiatr 1989, 26:500-504.
• [26]Aleman A, Verhaar HJ, de Haan EHF, De Vries WR, Samson MM, Drent ML, Van der Veen EA, Koppeschaar HP: Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab 1999, 84:471-475.
• [27]Rollero A, Murialdo G, Fonzi S, Garrone S, Gianelli MV, Gazzerro E, Barreca A, Polleri A: Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology 1998, 23:45-55.
• [28]Lackey BR, Gray SL, Henricks DM: Actions and interactions of the IGF system in Alzheimer’s Disease: review and hypotheses. Growth Horm IGF Res 2000, 10:1-13.
• [29]Vitiello MV, Moe KE, Merriam GR, Mazzoni G, Buchner DH, Schwartz RS: Growth hormone releasing hormone improves the cognition of healthy older adults. Neurobiol Aging 2006, 27:318-323.
• [30]Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM: A critical role for IGF-II in memory consolidation and enhancement. Nature 2011, 469:491-497.
• [31]Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr: Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998, 50:164-168.
• [32]Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ: Insulin dose–response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrino 2003, 28:809-822.
• [33]Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C: Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signaling. Neurobiol Aging 2010, 31:224-243.
• [34]Baker LD, Cross DJ, Minoshima S, Belongia D, Stennis Watson G, Craft S: Insulin resistance and alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011, 68:51-57.
• [35]Sims-Robinson C, Kim B, Rosko A, Feldman EL: How does diabetes accelerate Alzheimer disease pathology? Nat Rev Neurol 2010, 6:551-559.
• [36]Ott A, Stolk RP, van Harskamp F, Grobbee DE, Breteler MM: Diabetes mellitus and the risk of dementia: the Rotterdam study. Neurology 1999, 53:1937-1942.
• [37]de la Monte SM, Wands JR: Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008, 2:1101-1113.
• [38]Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB: Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? Brit J Clin Pharmaco 2011, 71:365-376.
• [39]Saleh N, Moutereau S, Durr A, Krystkowiak P, Azulay JP, Tranchant C, Broussolle E, Morin F, Bachoud-Lévi AC, Maison P: Neuroendocrine disturbances in huntington’s disease. PLoS One 2009, 3:e4962.
• [40]Ogishima S, Mizuno S, Kikuchi M, Miyashita A, Kuwano R, Tanaka H, Nakaya J: A map of Alzheimer’s disease-signaling pathways: a hope for drug target discovery. Clin Pharmacol Ther 2013, 93:399-401.
• [41]Hanisch D, Fundel K, Mevissen HT, Zimmer R, Fluck J: ProMiner: rule based protein and gene entity recognition. BMC Bioinformatics 2005, 6(Suppl 1):S14. BioMed Central Full Text
• [42]Friedrich CM, Dach H, Gattermayer T, Engelbrecht G, Benkner S, Hofmann-Apitius M: @neuLink: a service-oriented application for biomedical knowledge discovery. In Proceedings of the HealthGrid:2–4 June 2008. Edited by Tony S, Silverstein JC, Joel S, Yannick L, Mary K, Ian F, Vincent B, Robert Beck J. Chicago: IOS Press Amsterdam; 2008:165-172.
• [43]Potapov A, Liebich I, Dönitz J, Schwarzer K, Sasse N, Schoeps T, Crass T, Wingender E: EndoNet: an information resource about endocrine networks. Nucleic Acids Res 2006, 34:D540-D545.
• [44]Ramón AJG, Baldo O: Integration and Prediction of PPI Using Multiple Resources from Public Databases. J Proteomics Bioinform 2008, 1:166-187.
• [45]Killcoyne S, Carter GW, Smith J, Boyle J: Cytoscape: a community-based framework for network modeling. Methods Mol Biol 2009, 563:219-239.
• [46]Bastian M, Heymann S, Jacomy M: Gephi: an open source software for exploring and manipulating networks. In Proceedings of the Third International Conference on Weblogs and Social Media. Edited by Adar E, Hurst M, Finin T, Glance N, Nicolov N, Tseng B. San Jose, California: AAAI Press; 2009:361-362.
• [47]Su G, Kuchinsky A, Morris JH, States DJ, Meng F: GLay: community structure analysis of biological networks. Bioinformatics 2010, 26:3135-3137.
• [48]Nishimura D: BioCarta. Biotech Softw Internet Rep 2011, 2:117-120.
• [49]Frühbeck G: Intracellular signalling pathways activated by leptin. Biochem J 2006, 393:7-20.
• [50]Moeller LC, Cao X, Dumitrescu AM, Seo H, Refetoff S: Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor β through the phosphatidylinositol 3-kinase pathway. Nucl Recept Signal 2006, 4:e020.
• [51]QIAGEN Pathway Navigator. http://www.qiagen.com/products/genes%20and%20pathways/Pathway%20Details.aspx?pwid=124 webcite
• [52]Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI: Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 2003, 8:d1093-d1108.
• [53]Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP: Molecular signatures database (MSigDB) 3.0. Bioinformatics 2011, 27:1739-1740.
• [54]Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nat Protoc 2009, 4:44-57.
• [55]The Mouse Genome InformaticsDatabase. http://www.informatics.jax.org/ webcite
• [56]Younesi E, Toldo L, Müller B, Friedrich CM, Novac N, Scheer A, Hofmann-Apitius M, Fluck J: Mining biomarker information in biomedical literature. BMC Med Inform Decis 2012, 12:148. BioMed Central Full Text
• [57]The Kyoto Encyclopedia of Genes and Genomes Database. http://www.genome.jp/kegg/ webcite
• [58]The Genetic Association Database. geneticassociationdb.nih.gov
• [59]The Tissue Distribution Database. genome.dkfz-heidelberg.de/menu/tissue_db/
• [60]The DrugBank Database. http://www.drugbank.ca/ webcite
• [61]Barabasi AL, Oltvai ZN: Network biology: understanding the cell's functional organization. Nat Rev Genet 2004, 5:101-113.
• [62]Bossi A, Lehner B: Tissue specificity and the human protein interaction network. Mol Syst Biol 2009, 5:260.
• [63]Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW: The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1991, 1:103-116.
• [64]Davis JD, Podolanczuk A, Donahue JE, Stopa E, Hennessey JV, Luo LG, Lim YP, Stern RA: Thyroid hormone levels in the prefrontal cortex of post-mortem brains of Alzheimer’s disease patients. Curr Aging Sci 2008, 1:175.
• [65]Dai J, Buijs R, Swaab D: Glucocorticoidx hormone (cortisol) affects axonal transport in human cortex neurons but shows resistance in Alzheimer's disease. Br J Pharmacol 2004, 143:606-610.
• [66]Souza EB, Whitehouse PJ, Price DL, Vale WW: Abnormalities in Corticotropin-releasing Hormone (CRH) in Alzheimer's disease and other human disorders. Ann N Y Acad Sci 1987, 512:237-247.
• [67]Ishunina TA, Kamphorst W, Swaab DF: Metabolic alterations in the hypothalamus and basal forebrain in vascular dementia. J Neuropathol Exp Neurol 2004, 63:1243-1254.
• [68]Murialdo G, Zerbi F, Filippi U, Tosca P, Fonzi S, Di Paolo E, Costelli P, Porro S, Polleri A, Savoldi F: Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia. Neuropsychobiology 2008, 24:129-134.
• [69]Keenan PA, Ezzat WH, Ginsburg K, Moore GJ: Prefrontal cortex as the site of estrogen’s effect on cognition. Psychoneuroendocrino 2001, 26:577-590.
• [70]Watson GS, Bernhardt T, Reger MA, Cholerton BA, Baker D, Peskin ER, Asthana S, Plymate SR, Frölich L, Craft S: Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease. Neurobiol Aging 2006, 27:38-41.
• [71]Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Drent ML: Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study. Neuroendocrinology 2006, 83:12-19.
• [72]Zhu DF, Wang ZX, Zhang DR, Pan ZL, He S, Hu XP, Chen XC, Zhou JN: fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain 2006, 129:2923-2930.
• [73]Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA, McKeel D, Morris JC, Hulette CM, Schmechel D, Reiman EM, Rogers J, Stephan DA: Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol Genomics 2008, 33:240-256.
• [74]Liang D, Han G, Feng X, Sun J, Duan Y, Lei H: Concerted perturbation observed in a hub network in Alzheimer's disease. PLoS One 2012, 7:e40498.
• [75]MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK: Identifying off-target effects and hidden phenotypes of drugs in human cells. Nat Chem Biol 2006, 2:329-337.
• [76]Singh M, Sétáló G, Guan X, Warren M, Toran-Allerand CD: Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 1999, 19:1179-1188.
• [77]Craft S, Asthana S, Schellenberg G, Cherrier M, Baker LD, Newcomer J, Plymate S, Latendresse S, Petrova A, Raskind M, Peskind E, Lofgreen C, Grimwood K: Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrino 1999, 70:146-152.
• [78]Cardona-Gomez P, Perez M, Avila J, Garcia-Segura LM, Wandosell F: Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and β-catenin in the hippocampus. Mol Cell Neurosci 2004, 25:363-373.
• [79]Cuadrado A, Garcia-Fernandez LF, Imai T, Okano H, Munoz A: Regulation of tau RNA maturation by thyroid hormone is mediated by the neural RNA-binding protein Musashi-1. Mol Cell Neurosci 2002, 20:198-210.
• [80]Wang JZ, Wang ZF: Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 2006, 27:41-49.
• [81]Rissman RA, Lee KF, Vale W, Sawchenko PE: Corticotropin-releasing factor receptors differentially regulate stress-induced τ phosphorylation. J Neurosci 2007, 27:6552-6562.
• [82]Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, Kanba S, Kiyohara Y: Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 2011, 77:1126-1134.
• [83]Hsu CC, Wahlqvist ML, Lee MS, Tsai HN: Incidence of Dementia is Increased in Type 2 Diabetes and Reduced by the Use of Sulfonylureas and Metformin. J Alzheimers Dis 2011, 24:485-493.
• [84]Xu W, Qiu C, Gatz M, Pedersen NL, Johansson B, Fratiglioni L: Mid- and Late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 2009, 58:71-77.
• [85]Yaffe K, Falvey C, Hamilton N, Schwartz AV, Simonsick EM, Satterfield S, Cauley JA, Rosano C, Launer LJ, Strotmeyer ES, Harris TB: Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012, 9:1170-1175.
• [86]Cammarota M, Bevilaqua LRM, Ardenghi P, Paratcha G, Levi de Stein M, Izquierdo I, Medina JH: Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. Mol Brain Res 2000, 76:36-46.
• [87]Zhao WQ, Alkon DL: Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001, 177:125-134.
• [88]Zhao WQ, Chen H, Quon MJ, Alkon DL: Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004, 490:71-81.
• [89]Jucker M: The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 2010, 16:1210-1214.
• [90]Hölscher C: Neuronal mechanisms of memory formation: concepts of long term potentiation and beyond. Cambridge: Cambridge University Press; 2001.
• [91]Lynch MA: Long-term potentiation and memory. Physiol Rev 2004, 84:87-136.
• [92]Buxbaum JD, Cullen EI, Friedhoff LT: Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front Biosci 2002, 7:a50-a59.
• [93]Banks WA: Brain meets body: the blood–brain barrier as an endocrine interface. Endocrinology 2012, 9:4111-4119.