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Molecular Neurobiology

, Volume 55, Issue 7, pp 6007–6020 | Cite as

Expression of BC1 Impairs Spatial Learning and Memory in Alzheimer’s Disease Via APP Translation

  • Tongmei Zhang
  • Pei Pang
  • Zemin Fang
  • Yu Guo
  • Hao Li
  • Xinyan Li
  • Tian Tian
  • Xin Yang
  • Wenting Chen
  • Shu Shu
  • Na Tang
  • Jianhua Wu
  • Houze Zhu
  • Lei Pei
  • Dan LiuEmail author
  • Qing Tian
  • Jian Wang
  • Lin Wang
  • Ling-Qiang Zhu
  • Youming LuEmail author
Article

Abstract

Aggregation of amyloid-β (Aβ) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer’s disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aβ in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aβ peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aβ peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.

Keywords

BC1 FMRP Amyloid-β peptides App Alzheimer’s disease 

Abbreviations

Amyloid-β

APP

Amyloid precursor protein

FMRP

Fragile X syndrome protein

LTP

Long-term potentiation

lncRNA

Long noncoding RNA

LNA

Locked-nucleic acid-modified

Notes

Acknowledgments

We greatly thank Dr. Anbing Shi (Department of Biochemistry, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for the comments on manuscript. This work was supported by National Natural Science Foundation of China (grant number: 91632306 YL; 51627807 YL; 31721002 Y.L.; 31571039 LQZ; 81771150 LQZ; 91632114 LQZ). Top-Notch Young Talents Program of China of 2014 and Academic Frontier Youth Team of Huazhong University of Science and Technology to Dr. Ling-Qiang Zhu.

Supplementary material

12035_2017_820_MOESM1_ESM.pptx (1.5 mb)
ESM 1 (PPTX 1500 kb)

References

  1. 1.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706.  https://doi.org/10.1038/349704a0 CrossRefPubMedGoogle Scholar
  2. 2.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284):99–103CrossRefPubMedGoogle Scholar
  3. 3.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356.  https://doi.org/10.1126/science.1072994 CrossRefPubMedGoogle Scholar
  4. 4.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741CrossRefPubMedGoogle Scholar
  5. 5.
    Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE et al (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 14(6):419–427.  https://doi.org/10.1006/mcne.1999.0811 CrossRefPubMedGoogle Scholar
  6. 6.
    Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E et al (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407(6800):48–54.  https://doi.org/10.1038/35024009 CrossRefPubMedGoogle Scholar
  7. 7.
    Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature 422(6930):438–441.  https://doi.org/10.1038/nature01506 CrossRefPubMedGoogle Scholar
  8. 8.
    Sadleir KR, Eimer WA, Cole SL, Vassar R (2015) Abeta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level. Mol Neurodegener 10:1.  https://doi.org/10.1186/1750-1326-10-1 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Akaaboune M, Allinquant B, Farza H, Roy K, Magoul R, Fiszman M, Festoff BW, Hantai D (2000) Developmental regulation of amyloid precursor protein at the neuromuscular junction in mouse skeletal muscle. Mol Cell Neurosci 15(4):355–367CrossRefPubMedGoogle Scholar
  10. 10.
    Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37(6):925–937CrossRefPubMedGoogle Scholar
  11. 11.
    Klevanski M, Herrmann U, Weyer SW, Fol R, Cartier N, Wolfer DP, Caldwell JH, Korte M et al (2015) The APP intracellular domain is required for normal synaptic morphology, synaptic plasticity, and hippocampus-dependent behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(49):16018–16033.  https://doi.org/10.1523/JNEUROSCI.2009-15.2015 CrossRefGoogle Scholar
  12. 12.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791.  https://doi.org/10.1126/science.1074069 CrossRefPubMedGoogle Scholar
  13. 13.
    Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120(4):545–555.  https://doi.org/10.1016/j.cell.2005.02.008 CrossRefPubMedGoogle Scholar
  14. 14.
    Tu S, Okamoto S, Lipton SA, Xu H (2014) Oligomeric Abeta-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 9:48.  https://doi.org/10.1186/1750-1326-9-48 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Audrain M, Fol R, Dutar P, Potier B, Billard JM, Flament J, Alves S, Burlot MA et al (2016) Alzheimer’s disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression. Mol Neurodegener 11:5.  https://doi.org/10.1186/s13024-016-0070-y CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3.  https://doi.org/10.1186/1756-6606-4-3 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509.  https://doi.org/10.1038/nrn2168 CrossRefPubMedGoogle Scholar
  18. 18.
    Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M et al (1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7(1):43–51CrossRefPubMedGoogle Scholar
  19. 19.
    Haass C, De Strooper B (1999) The presenilins in Alzheimer’s disease—proteolysis holds the key. Science 286(5441):916–919CrossRefPubMedGoogle Scholar
  20. 20.
    Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE Jr, Wang Q, Roach AH et al (2000) Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J Biol Chem 275(44):34086–34091.  https://doi.org/10.1074/jbc.M005430200 CrossRefPubMedGoogle Scholar
  21. 21.
    De Strooper B (2007) Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8(2):141–146.  https://doi.org/10.1038/sj.embor.7400897 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kanekiyo T, Xu H, Bu G (2014) ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81(4):740–754.  https://doi.org/10.1016/j.neuron.2014.01.045 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118.  https://doi.org/10.1038/nrneurol.2012.263 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhao N, Liu CC, Qiao W, Bu G (2017) Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry.  https://doi.org/10.1016/j.biopsych.2017.03.003
  25. 25.
    Westmark CJ, Malter JS (2012) The regulation of AbetaPP expression by RNA-binding proteins. Ageing Res Rev 11(4):450–459.  https://doi.org/10.1016/j.arr.2012.03.005 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yang Y, Shu X, Liu D, Shang Y, Wu Y, Pei L, Xu X, Tian Q et al (2012) EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73(4):774–788.  https://doi.org/10.1016/j.neuron.2012.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian MM, Balel C, Wang M et al (2010) DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140(2):222–234.  https://doi.org/10.1016/j.cell.2009.12.055 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang X, Pei L, Yan H, Wang Z, Wei N, Wang S, Yang X, Tian Q et al (2014) Intervention of death-associated protein kinase 1-p53 interaction exerts the therapeutic effects against stroke. Stroke 45(10):3089–3091.  https://doi.org/10.1161/STROKEAHA.114.006348 CrossRefPubMedGoogle Scholar
  29. 29.
    Liu D, Wei N, Man HY, Lu Y, Zhu LQ, Wang JZ (2015) The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling. Cell Death Differ 22(4):583–596.  https://doi.org/10.1038/cdd.2014.195 CrossRefPubMedGoogle Scholar
  30. 30.
    Peng PL, Zhong X, Tu W, Soundarapandian MM, Molner P, Zhu D, Lau L, Liu S et al (2006) ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49(5):719–733.  https://doi.org/10.1016/j.neuron.2006.01.025 CrossRefPubMedGoogle Scholar
  31. 31.
    Yang X, Yao C, Tian T, Li X, Yan H, Wu J, Li H, Pei L et al (2016) A novel mechanism of memory loss in Alzheimer’s disease mice via the degeneration of entorhinal-CA1 synapses. Mol Psychiatry.  https://doi.org/10.1038/mp.2016.151
  32. 32.
    Shu S, Zhu H, Tang N, Chen W, Li X, Li H, Pei L, Liu D et al (2016) Selective degeneration of entorhinal-CA1 synapses in Alzheimer’s disease via activation of DAPK1. J Neurosci 36(42):10843–10852.  https://doi.org/10.1523/JNEUROSCI.2258-16.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fang M, Zhang P, Zhao Y, Liu X (2017) Bioinformatics and co-expression network analysis of differentially expressed lncRNAs and mRNAs in hippocampus of APP/PS1 transgenic mice with Alzheimer disease. Am J Transl Res 9(3):1381–1391PubMedPubMedCentralGoogle Scholar
  34. 34.
    Kelleher RJ 3rd, Govindarajan A, Jung HY, Kang H, Tonegawa S (2004) Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116(3):467–479CrossRefPubMedGoogle Scholar
  35. 35.
    Schreiweis C, Bornschein U, Burguiere E, Kerimoglu C, Schreiter S, Dannemann M, Goyal S, Rea E et al (2014) Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance. Proc Natl Acad Sci U S A 111(39):14253–14258.  https://doi.org/10.1073/pnas.1414542111 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Spinney L (2014) Alzheimer’s disease: the forgetting gene. Nature 510(7503):26–28.  https://doi.org/10.1038/510026a CrossRefPubMedGoogle Scholar
  37. 37.
    Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108(5):689–703CrossRefPubMedGoogle Scholar
  38. 38.
    Kim MY, Hwang DW, Li F, Choi Y, Byun JW, Kim D, Kim JE, Char K et al (2016) Detection of intra-brain cytoplasmic 1 (BC1) long noncoding RNA using graphene oxide-fluorescence beacon detector. Sci Rep 6:22552.  https://doi.org/10.1038/srep22552 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lacoux C, Di Marino D, Boyl PP, Zalfa F, Yan B, Ciotti MT, Falconi M, Urlaub H et al (2012) BC1-FMRP interaction is modulated by 2′-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses. Nucleic Acids Res 40(9):4086–4096.  https://doi.org/10.1093/nar/gkr1254 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (2003) The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112(3):317–327CrossRefPubMedGoogle Scholar
  41. 41.
    Zalfa F, Adinolfi S, Napoli I, Kuhn-Holsken E, Urlaub H, Achsel T, Pastore A, Bagni C (2005) Fragile X mental retardation protein (FMRP) binds specifically to the brain cytoplasmic RNAs BC1/BC200 via a novel RNA-binding motif. J Biol Chem 280(39):33403–33410.  https://doi.org/10.1074/jbc.M504286200 CrossRefPubMedGoogle Scholar
  42. 42.
    Westmark CJ, Malter JS (2007) FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol 5(3):e52.  https://doi.org/10.1371/journal.pbio.0050052 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang H, Iacoangeli A, Popp S, Muslimov IA, Imataka H, Sonenberg N, Lomakin IB, Tiedge H (2002) Dendritic BC1 RNA: functional role in regulation of translation initiation. J Neurosci 22(23):10232–10241CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Tiedge H, Fremeau RT Jr, Weinstock PH, Arancio O, Brosius J (1991) Dendritic location of neural BC1 RNA. Proc Natl Acad Sci U S A 88(6):2093–2097CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chicurel ME, Terrian DM, Potter H (1993) mRNA at the synapse: analysis of a synaptosomal preparation enriched in hippocampal dendritic spines. The Journal of neuroscience : the official journal of the Society for Neuroscience 13(9):4054–4063CrossRefGoogle Scholar
  46. 46.
    Rao A, Steward O (1993) Evaluation of RNAs present in synaptodendrosomes: Dendritic, glial, and neuronal cell body contribution. J Neurochem 61(3):835–844CrossRefPubMedGoogle Scholar
  47. 47.
    Wang H, Iacoangeli A, Lin D, Williams K, Denman RB, Hellen CU, Tiedge H (2005) Dendritic BC1 RNA in translational control mechanisms. J Cell Biol 171(5):811–821.  https://doi.org/10.1083/jcb.200506006 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Mus E, Hof PR, Tiedge H (2007) Dendritic BC200 RNA in aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A 104(25):10679–10684.  https://doi.org/10.1073/pnas.0701532104 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Verheij C, Bakker CE, de Graaff E, Keulemans J, Willemsen R, Verkerk AJ, Galjaard H, Reuser AJ et al (1993) Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 363(6431):722–724.  https://doi.org/10.1038/363722a0 CrossRefPubMedGoogle Scholar
  50. 50.
    Weiler IJ, Irwin SA, Klintsova AY, Spencer CM, Brazelton AD, Miyashiro K, Comery TA, Patel B et al (1997) Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci U S A 94(10):5395–5400CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60(2):201–214.  https://doi.org/10.1016/j.neuron.2008.10.004 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99(11):7746–7750.  https://doi.org/10.1073/pnas.122205699 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Lee HY, Ge WP, Huang W, He Y, Wang GX, Rowson-Baldwin A, Smith SJ, Jan YN et al (2011) Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. Neuron 72(4):630–642.  https://doi.org/10.1016/j.neuron.2011.09.033 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Tongmei Zhang
    • 1
    • 2
  • Pei Pang
    • 1
    • 2
  • Zemin Fang
    • 3
  • Yu Guo
    • 1
    • 2
  • Hao Li
    • 1
    • 2
  • Xinyan Li
    • 1
    • 2
  • Tian Tian
    • 1
    • 2
  • Xin Yang
    • 1
    • 2
  • Wenting Chen
    • 1
    • 2
  • Shu Shu
    • 1
    • 2
  • Na Tang
    • 1
    • 2
  • Jianhua Wu
    • 1
    • 2
  • Houze Zhu
    • 1
    • 2
  • Lei Pei
    • 2
    • 4
  • Dan Liu
    • 2
    • 5
    Email author
  • Qing Tian
    • 2
    • 6
  • Jian Wang
    • 2
    • 7
  • Lin Wang
    • 2
    • 7
  • Ling-Qiang Zhu
    • 2
    • 6
  • Youming Lu
    • 1
    • 2
    Email author
  1. 1.Department of Physiology, School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.The Institute of Brain ResearchHuazhong University of Science and TechnologyWuhanChina
  3. 3.Department of Cardiothoracic Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  4. 4.Department of Neurobiology, School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  5. 5.Department of Genetics, School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  6. 6.Department of Pathophysiology, School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  7. 7.Research Center for Tissue Engineering and Regenerative Medicine, Department of Clinical Laboratory, The Union HospitalHuazhong University of Science and TechnologyWuhanChina

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