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Age- and Nicotine-Associated Gene Expression Changes in the Hippocampus of APP/PS1 Mice

  • Jie Yang
  • Yan Long
  • De-Mei Xu
  • Bing-Lin Zhu
  • Xiao-Juan Deng
  • Zhen Yan
  • Fei Sun
  • Guo-Jun ChenEmail author
Article

Abstract

The etiology of Alzheimer’s disease (AD) has been intensively studied. However, little is known about the molecular alterations in early-stage and late-stage AD. Hence, we performed RNA sequencing and assessed differentially expressed genes (DEGs) in the hippocampus of 18-month and 7-month-old APP/PS1 mice. Moreover, the DEGs induced by treatment with nicotine, the nicotinic acetylcholine receptor agonist that is known to improve cognition in AD, were also analyzed in old and young APP/PS1 mice. When comparing old APP/PS1 mice with their younger littermates, we found an upregulation in genes associated with calcium overload, immune response, cancer, and synaptic function; the transcripts of 14 calcium ion channel subtypes were significantly increased in aged mice. In contrast, the downregulated genes in aged mice were associated with ribosomal components, mitochondrial respiratory chain complex, and metabolism. Through comparison with DEGs in normal aging from previous reports, we found that changes in calcium channel genes remained one of the prominent features in aged APP/PS1 mice. Nicotine treatment also induced changes in gene expression. Indeed, nicotine augmented glycerolipid metabolism, but inhibited PI3K and MAPK signaling in young mice. In contrast, nicotine affected genes associated with cell senescence and death in old mice. Our study suggests a potential network connection between calcium overload and cellular signaling, in which additional nicotinic activation might not be beneficial in late-stage AD.

Keywords

Alzheimer’s disease Transcriptome Hippocampus Nicotine Alternative splicing Calcium overload 

Notes

Acknowledgments

This work was supported by National Nature Science Foundation of China grants (numbers 81171197 & 81220108010) to G-J C. G-J Chen and Z Yan designed research; J Yang performed research; Y Long, D-M Xu, B-L Zhu, X-J Deng and F Sun provided assistance; J Yang analyzed data; G-J Chen and J Yang wrote the paper.

Funding

This work was supported by National Natural Science Foundation of China (NSFC) grants (numbers 81171197 & 81220108010) to G-J Chen.

Compliance with Ethical Standards

All protocols were approved by the Commission of Chongqing Medical University for ethics of experiments on animals and were in accordance with international standards.

Conflict of Interest

The authors declare that they have no conflict of interest.

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References

  1. Balsara RD, Ploplis VA (2008) Plasminogen activator inhibitor-1: the double-edged sword in apoptosis. Thromb Haemost 100:1029–1036CrossRefGoogle Scholar
  2. Barbash S, Soreq H (2012) Threshold-independent meta-analysis of Alzheimer's disease transcriptomes shows progressive changes in hippocampal functions, epigenetics and microRNA regulation. Curr Alzheimer Res 9:425–435CrossRefGoogle Scholar
  3. Barker R, Kehoe PG, Love S (2012) Activators and inhibitors of the plasminogen system in Alzheimer's disease. J Cell Mol Med 16:865–876.  https://doi.org/10.1111/j.1582-4934.2011.01394.x CrossRefGoogle Scholar
  4. Benjamini Y, Hochberg Y (1995) Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B Methodol 57:289–300Google Scholar
  5. Berchtold NC et al (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci U S A 105:15605–15610.  https://doi.org/10.1073/pnas.0806883105 CrossRefGoogle Scholar
  6. Berchtold NC, Sabbagh MN, Beach TG, Kim RC, Cribbs DH, Cotman CW (2014) Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. Neurobiol Aging 35:1961–1972.  https://doi.org/10.1016/j.neurobiolaging.2014.03.031 CrossRefGoogle Scholar
  7. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31:454–463.  https://doi.org/10.1016/j.tins.2008.06.005 CrossRefGoogle Scholar
  8. Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC, Landfield PW (2003) Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 23:3807–3819CrossRefGoogle Scholar
  9. Blalock EM et al (2005) Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: statistical reliability and functional correlation. Ageing Res Rev 4:481–512.  https://doi.org/10.1016/j.arr.2005.06.006 CrossRefGoogle Scholar
  10. Cheng XR, Cui XL, Zheng Y, Zhang GR, Li P, Huang H, Zhao YY, Bo XC, Wang SQ, Zhou WX, Zhang YX (2013) Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model. Front Aging Neurosci 5:65.  https://doi.org/10.3389/fnagi.2013.00065 CrossRefGoogle Scholar
  11. Ding Q, Markesbery WR, Chen Q, Li F, Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci 25:9171–9175.  https://doi.org/10.1523/jneurosci.3040-05.2005 CrossRefGoogle Scholar
  12. Draghici S et al (2007) A systems biology approach for pathway level analysis. Genome Res 17:1537–1545.  https://doi.org/10.1101/gr.6202607 CrossRefGoogle Scholar
  13. Durazzo TC, Mattsson N, Weiner MW (2014) Smoking and increased Alzheimer's disease risk: a review of potential mechanisms. Alzheimers Dement 10:S122–S145.  https://doi.org/10.1016/j.jalz.2014.04.009 CrossRefGoogle Scholar
  14. Dutto I, Tillhon M, Cazzalini O, Stivala LA, Prosperi E (2015) Biology of the cell cycle inhibitor p21(CDKN1A): molecular mechanisms and relevance in chemical toxicology. Arch Toxicol 89:155–178.  https://doi.org/10.1007/s00204-014-1430-4 CrossRefGoogle Scholar
  15. Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW (2016) Estrogens as neuroprotectants: estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol.  https://doi.org/10.1016/j.pneurobio.2015.12.008
  16. Eren M, Boe AE, Klyachko EA, Vaughan DE (2014) Role of plasminogen activator inhibitor-1 in senescence and aging. Semin Thromb Hemost 40:645–651.  https://doi.org/10.1055/s-0034-1387883 CrossRefGoogle Scholar
  17. Espeland MA et al (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative memory study. JAMA 291:2959–2968.  https://doi.org/10.1001/jama.291.24.2959 CrossRefGoogle Scholar
  18. Gao L, Hidalgo-Figueroa M, Escudero LM, Diaz-Martin J, Lopez-Barneo J, Pascual A (2013) Age-mediated transcriptomic changes in adult mouse substantia nigra. PLoS One 8:e62456.  https://doi.org/10.1371/journal.pone.0062456 CrossRefGoogle Scholar
  19. Gatta V, D'Aurora M, Granzotto A, Stuppia L, Sensi SL (2014) Early and sustained altered expression of aging-related genes in young 3xTg-AD mice. Cell Death Dis 5:e1054.  https://doi.org/10.1038/cddis.2014.11 CrossRefGoogle Scholar
  20. Ginsberg SD, Alldred MJ, Che S (2012) Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer's disease. Neurobiol Dis 45:99–107.  https://doi.org/10.1016/j.nbd.2011.07.013 CrossRefGoogle Scholar
  21. Giovannini MG et al (2008) Differential activation of mitogen-activated protein kinase signalling pathways in the hippocampus of CRND8 transgenic mouse, a model of Alzheimer's disease. neuroscience 153:618–633.  https://doi.org/10.1016/j.neuroscience.2008.02.061 CrossRefGoogle Scholar
  22. Henley BM et al (2013) Transcriptional regulation by nicotine in dopaminergic neurons. Biochem Pharmacol 86:1074–1083.  https://doi.org/10.1016/j.bcp.2013.07.031 CrossRefGoogle Scholar
  23. Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J (2014) The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 26:2694–2701.  https://doi.org/10.1016/j.cellsig.2014.08.019 CrossRefGoogle Scholar
  24. Hilario MR, Turner JR, Blendy JA (2012) Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. Neuropsychopharmacology 37:2661–2670.  https://doi.org/10.1038/npp.2012.130 CrossRefGoogle Scholar
  25. Hu S et al (2014) Transcriptomic changes during the pre-receptive to receptive transition in human endometrium detected by RNA-Seq. J Clin Endocrinol Metab 99:E2744–E2753.  https://doi.org/10.1210/jc.2014-2155 CrossRefGoogle Scholar
  26. Huang Y, Sun X, Hu G (2011) An integrated genetics approach for identifying protein signal pathways of Alzheimer's disease. Comput Methods Biomech Biomed Engin 14:371–378.  https://doi.org/10.1080/10255842.2010.482525 CrossRefGoogle Scholar
  27. Jankowsky JL et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170.  https://doi.org/10.1093/hmg/ddh019 CrossRefGoogle Scholar
  28. Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M (2004) The KEGG resource for deciphering the genome. Nucleic Acids Res 32:D277–D280.  https://doi.org/10.1093/nar/gkh063 CrossRefGoogle Scholar
  29. Kedmi M, Orr-Urtreger A (2011) The effects of aging vs. alpha7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency. Age (Dordr) 33:1–13.  https://doi.org/10.1007/s11357-010-9155-7 CrossRefGoogle Scholar
  30. Lanni C, Racchi M, Memo M, Govoni S, Uberti D (2012) p53 at the crossroads between cancer and neurodegeneration. Free Radic Biol Med 52:1727–1733.  https://doi.org/10.1016/j.freeradbiomed.2012.02.034 CrossRefGoogle Scholar
  31. LaPak KM, Burd CE (2014) The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res 12:167–183.  https://doi.org/10.1158/1541-7786.MCR-13-0350 CrossRefGoogle Scholar
  32. Leng N et al (2013) EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments. bioinformatics 29:1035–1043.  https://doi.org/10.1093/bioinformatics/btt087 CrossRefGoogle Scholar
  33. Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 184:523–539.  https://doi.org/10.1007/s00213-005-0164-7 CrossRefGoogle Scholar
  34. Li C, Li H (2008) Network-constrained regularization and variable selection for analysis of genomic data. bioinformatics 24:1175–1182.  https://doi.org/10.1093/bioinformatics/btn081 CrossRefGoogle Scholar
  35. Li MD, Konu O, Kane JK, Becker KG (2002) Microarray technology and its application on nicotine research. Mol Neurobiol 25:265–285CrossRefGoogle Scholar
  36. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891.  https://doi.org/10.1038/nature02661 CrossRefGoogle Scholar
  37. Marighetto A, Valerio S, Desmedt A, Philippin JN, Trocme-Thibierge C, Morain P (2008) Comparative effects of the alpha7 nicotinic partial agonist, S 24795, and the cholinesterase inhibitor, donepezil, against aging-related deficits in declarative and working memory in mice. Psychopharmacology 197:499–508.  https://doi.org/10.1007/s00213-007-1063-x CrossRefGoogle Scholar
  38. Marks MJ, Rowell PP, Cao JZ, Grady SR, McCallum SE, Collins AC (2004) Subsets of acetylcholine-stimulated 86Rb+ efflux and [125I]-epibatidine binding sites in C57BL/6 mouse brain are differentially affected by chronic nicotine treatment. Neuropharmacology 46:1141–1157.  https://doi.org/10.1016/j.neuropharm.2004.02.009 CrossRefGoogle Scholar
  39. Miller JA, Horvath S, Geschwind DH (2010) Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci U S A 107:12698–12703.  https://doi.org/10.1073/pnas.0914257107 CrossRefGoogle Scholar
  40. Mills JD, Janitz M (2012) Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases. Neurobiol Aging 33:1012 e1011–1012 e1024.  https://doi.org/10.1016/j.neurobiolaging.2011.10.030 CrossRefGoogle Scholar
  41. Mudo G, Belluardo N, Fuxe K (2007) Nicotinic receptor agonists as neuroprotective/neurotrophic drugs. Progress in molecular mechanisms. J Neural Transm 114:135–147.  https://doi.org/10.1007/s00702-006-0561-z CrossRefGoogle Scholar
  42. O’ Neill C (2013) PI3-kinase/Akt/mTOR signaling: Impaired on/off switches in aging, cognitive decline and Alzheimer's disease. Exp Gerontol 48:647–653.  https://doi.org/10.1016/j.exger.2013.02.025 CrossRefGoogle Scholar
  43. Oh J, Lee HJ, Song JH, Park SI, Kim H (2014) Plasminogen activator inhibitor-1 as an early potential diagnostic marker for Alzheimer's disease. Exp Gerontol 60:87–91.  https://doi.org/10.1016/j.exger.2014.10.004 CrossRefGoogle Scholar
  44. Parachikova A et al (2007) Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging 28:1821–1833.  https://doi.org/10.1016/j.neurobiolaging.2006.08.014 CrossRefGoogle Scholar
  45. Paxinos G, Franklin KBJ (2001) The Mouse Brain in Stereotaxic Coordinates. Academic Press, New York, pp 381–388.  https://doi.org/10.1124/jpet.106.104414 Google Scholar
  46. Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, Roques P, Fuldner RA, Johnston J, Cowburn R, Forsell C, Axelman K, Lilius L, Houlden H, Karran E, Roberts GW, Rossor M, Adams MD, Hardy J, Goate A, Lannfelt L, Hutton M (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7:297–301CrossRefGoogle Scholar
  47. Phillips M, Boman E, Osterman H, Willhite D, Laska M (2011) Olfactory and visuospatial learning and memory performance in two strains of Alzheimer's disease model mice--a longitudinal study. PLoS One 6:e19567.  https://doi.org/10.1371/journal.pone.0019567 CrossRefGoogle Scholar
  48. Pike CJ, Carroll JC, Rosario ER, Barron AM (2009) Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol 30:239–258.  https://doi.org/10.1016/j.yfrne.2009.04.015 CrossRefGoogle Scholar
  49. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362:329–344.  https://doi.org/10.1056/NEJMra0909142 CrossRefGoogle Scholar
  50. Ramamoorthy M et al (2012) Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype. Free Radic Biol Med 53:1371–1380.  https://doi.org/10.1016/j.freeradbiomed.2012.07.018 CrossRefGoogle Scholar
  51. Reddy PH, McWeeney S (2006) Mapping cellular transcriptosomes in autopsied Alzheimer's disease subjects and relevant animal models. Neurobiol Aging 27:1060–1077.  https://doi.org/10.1016/j.neurobiolaging.2005.04.014 CrossRefGoogle Scholar
  52. Richardson RJ, Hein ND, Wijeyesakere SJ, Fink JK, Makhaeva GF (2013) Neuropathy target esterase (NTE): overview and future. Chem Biol Interact 203:238–244.  https://doi.org/10.1016/j.cbi.2012.10.024 CrossRefGoogle Scholar
  53. Ryan MM, Guevremont D, Luxmanan C, Abraham WC, Williams JM (2015) Aging alters long-term potentiation--related gene networks and impairs synaptic protein synthesis in the rat hippocampus. Neurobiol Aging 36:1868–1880.  https://doi.org/10.1016/j.neurobiolaging.2015.01.012 CrossRefGoogle Scholar
  54. Sadritdinova AF et al (2014) A new reliable reference gene UBA52 for quantitative real-time polymerase chain reaction studies in pyloric cecal tissues of the starfish Asterias rubens. Genet Mol Res 13:3972–3980.  https://doi.org/10.4238/2014.May.23.8 CrossRefGoogle Scholar
  55. Satoh J, Yamamoto Y, Asahina N, Kitano S, Kino Y (2014) RNA-Seq data mining: downregulation of NeuroD6 serves as a possible biomarker for alzheimer's disease brains. Dis Markers 2014:123165.  https://doi.org/10.1155/2014/123165 CrossRefGoogle Scholar
  56. Shannon P et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504.  https://doi.org/10.1101/gr.1239303 CrossRefGoogle Scholar
  57. Shumaker SA et al (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative memory study. JAMA 291:2947–2958.  https://doi.org/10.1001/jama.291.24.2947 CrossRefGoogle Scholar
  58. Silva AR et al (2014) Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease. PLoS One 9:e99897.  https://doi.org/10.1371/journal.pone.0099897 CrossRefGoogle Scholar
  59. Simpson JE et al (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer's pathology and APOE genotype. Neurobiol Aging 32:1795–1807.  https://doi.org/10.1016/j.neurobiolaging.2011.04.013 CrossRefGoogle Scholar
  60. Sullivan KD, Gallant-Behm CL, Henry RE, Fraikin JL, Espinosa JM (2012) The p53 circuit board. Biochim Biophys Acta 1825:229–244.  https://doi.org/10.1016/j.bbcan.2012.01.004 Google Scholar
  61. Tabatabaeian H, Hojati Z (2013) Assessment of HER-2 gene overexpression in Isfahan province breast cancer patients using real time RT-PCR and immunohistochemistry. Gene 531:39–43.  https://doi.org/10.1016/j.gene.2013.08.040 CrossRefGoogle Scholar
  62. Tazi J, Bakkour N, Stamm S (2009) Alternative splicing and disease. Biochim Biophys Acta 1792:14–26.  https://doi.org/10.1016/j.bbadis.2008.09.017 CrossRefGoogle Scholar
  63. Toescu EC, Verkhratsky A, Landfield PW (2004) Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci 27:614–620.  https://doi.org/10.1016/j.tins.2004.07.010 CrossRefGoogle Scholar
  64. Trapnell C et al (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and cufflinks. Nat Protoc 7:562–578.  https://doi.org/10.1038/nprot.2012.016 CrossRefGoogle Scholar
  65. Wang W et al (2014) Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor. BMC Med Genet 7:49.  https://doi.org/10.1186/1755-8794-7-49 Google Scholar
  66. Wang YF et al (2012) iPSCs are transcriptionally and post-transcriptionally indistinguishable from fESCs. Front Biosci (Landmark Ed) 17:1659–1668CrossRefGoogle Scholar
  67. Webster B, Hansen L, Adame A, Crews L, Torrance M, Thal L, Masliah E (2006) Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease. J Neuropathol Exp Neurol 65:142–151.  https://doi.org/10.1097/01.jnen.0000199599.63204.6f CrossRefGoogle Scholar
  68. Wlodarczyk J, Mukhina I, Kaczmarek L, Dityatev A (2011) Extracellular matrix molecules, their receptors, and secreted proteases in synaptic plasticity. Dev Neurobiol 71:1040–1053.  https://doi.org/10.1002/dneu.20958 CrossRefGoogle Scholar
  69. Yu JT, Chang RC, Tan L (2009) Calcium dysregulation in Alzheimer's disease: from mechanisms to therapeutic opportunities. Prog Neurobiol 89:240–255.  https://doi.org/10.1016/j.pneurobio.2009.07.009 CrossRefGoogle Scholar
  70. Zhang R, Zhang Q, Niu J, Lu K, Xie B, Cui D, Xu S (2014) Screening of microRNAs associated with Alzheimer's disease using oxidative stress cell model and different strains of senescence accelerated mice. J Neurol Sci 338:57–64.  https://doi.org/10.1016/j.jns.2013.12.017 CrossRefGoogle Scholar
  71. Zhao W et al (2015) Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects. Neuropsychiatr Dis Treat 11:565–574.  https://doi.org/10.2147/NDT.S74898 Google Scholar
  72. Zhou X et al (2014) Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation. Nucleic Acids Res 42:4019–4030.  https://doi.org/10.1093/nar/gkt1387 CrossRefGoogle Scholar
  73. Zhu Z et al (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both beta-amyloid production and clearance. J Neurosci 33:13138–13149.  https://doi.org/10.1523/JNEUROSCI.4790-12.2013 CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of NeurologyThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of NeurologyChongqingChina
  2. 2.Department of Physiology and BiophysicsState University of New York at BuffaloBuffaloUSA
  3. 3.Department of PhysiologyWayne State University School of MedicineDetroitUSA

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