Advertisement

Neurochemical Research

, Volume 44, Issue 3, pp 683–691 | Cite as

Regulation of Neurotransmitter Release by Amyloid Precursor Protein Through Synapsin Phosphorylation

  • An Liu
  • Ying Zhang
  • Lifang Han
  • Guiqin He
  • Wei Xie
  • Zikai Zhou
  • Zhengping JiaEmail author
Original Paper

Abstract

Abnormal processing of amyloid precursor protein (APP) and aggregation of the Aβ peptide are known to play a key role in the pathogenesis of Alzheimer disease, but the function of endogenous APP under normal physiological conditions remains poorly understood. In this study, we investigated presynaptic changes in APP knockout (KO) mice. We demonstrate that both sucrose-induced neurotransmission and synaptic depletion in response to high frequency stimulation are significantly enhanced in APP KO compared to wild type littermates. In addition, the level of phosphorylated forms of synapsins, but not total synapsins, is elevated in the KO mice. Furthermore, we show that the inhibition of L-type calcium channels normalizes phosphorylated synapsins and slows down the high frequency induced synaptic depletion in APP KO mice. These results suggest a new mechanism by which APP regulates synaptic vesicle dynamics through synapsin-dependent phosphorylation.

Keywords

Alzheimer disease Amyloid precursor protein Synaptic depletion Synapsin Ca2+ channel 

Notes

Acknowledgements

We thank all members of Jia lab for their technical assistance and comments on the manuscript.

Funding

This work was supported by Grants from the Canadian Institutes of Health Research (CIHR, MOP119421, ZPJ), Canadian Natural Science and Engineering Research Council (NSERC, RGPIN341498, ZPJ), Natural Science Foundation of China (NSFC 31200805, ZZ), NSFC and CIHR Joint Health Research Initiative Program (81161120543, WX and CCI117959, ZPJ), National Postdoctoral Program for Innovative Talents (1131000,047, AL) and Brain Canada (ZPJ).

References

  1. 1.
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid β-protein dimers isolated directly from alzheimer brains impair synaptic plasticity and memory. Nat Med 14:837CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein e genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:9649–9653CrossRefPubMedGoogle Scholar
  3. 3.
    Mckhann GM, Knopman DS, Chertkow H, Hyman BT Jr, Kawas CH, Jack CR, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925CrossRefPubMedGoogle Scholar
  5. 5.
    Nilsberth C, Westlinddanielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced A|[beta]| protofibril formation. Nat Neurosci 4:887CrossRefPubMedGoogle Scholar
  6. 6.
    Oddo S, Caccamo AShepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, Laferla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421CrossRefPubMedGoogle Scholar
  7. 7.
    Szodorai A, Kuan YH, Hunzelmann S, Engel U, Sakane A, Sasaki T, Takai Y, Kirsch J, Müller U, Beyreuther K (2009) APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle. J Neurosci 29:14534–14544CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sabo SL, Ikin AF, Buxbaum JD, Greengard P (2003) The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J Neurosci 23:5407–5415CrossRefPubMedGoogle Scholar
  9. 9.
    Cheung HN, Dunbar C, Mórotz GM, Cheng WH, Chan HY, Miller CC, Lau KF (2014) FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth. FASEB J 28:337–349CrossRefPubMedGoogle Scholar
  10. 10.
    Magara F, Wolfer DP (1999) Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the β-amyloid-precursor protein. Proc Natl Acad Sci USA 96:4656-4661CrossRefGoogle Scholar
  11. 11.
    Osterhout JA, Stafford BK, Nguyen PL, Yoshihara Y, Huberman AD (2015) Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron 86:985–999CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Olsen O, Kallop DY, Mclaughlin T, Huntwork-Rodriguez S, Wu Z, Duggan CD, Simon DJ, Lu Y, Easley-Neal C, Takeda K (2014) Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of β-secretase. J Neurosci 34:6438–6447CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tyan SH, Shih AY, Walsh JJ, Maruyama H, Sarsoza F, Ku L, Eggert S, Hof PR, Koo EH, Dickstein DL (2012) Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cel Neurosci 51:43CrossRefGoogle Scholar
  14. 14.
    Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression. Acta Neuropathol Commun 2:36CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Perez R, Zheng H, Der Ploeg LHTV, Koo EH (1997) The β-Amyloid precursor protein of Alzheimer’s disease enhances neuron viability and modulates neuronal polarity. J Neurosci 17:9407–9414CrossRefPubMedGoogle Scholar
  16. 16.
    Matrone C, Luvisetto S, La Rosa LR, Tamayev R, Pignataro A, Canu N, Yang L, Barbagallo APM, Biundo F, Lombino F (2012) Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 11:1084–1093CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hick M, Herrmann U, Weyer SW, Mallm JP, Tschäpe JA, Borgers M, Mercken M, Roth FC, Draguhn A, Slomianka L (2015) Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity. Acta Neuropathol 129:161–162CrossRefPubMedGoogle Scholar
  18. 18.
    Lee KJ, Moussa CE, Lee Y, Sung Y, Howell BW, Turner RS, Pak DT, Hoe HS (2010) Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines. Neuroscience 169:344–356CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Terry RD, Masliah E, Salmon DP, Butters N, Deteresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572CrossRefPubMedGoogle Scholar
  20. 20.
    De SB, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164:603CrossRefGoogle Scholar
  21. 21.
    Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M (2007) The secreted β-Amyloid precursor protein ectodomain APPsα is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 27:7817–7826CrossRefPubMedGoogle Scholar
  22. 22.
    Dawson GR, Seabrook GR, Zheng H, Smith DW, Graham S, O’Dowd G, Bowery BJ, Boyce S, Trumbauer ME, Chen HY (1999) Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein. Neuroscience 90:1–13CrossRefPubMedGoogle Scholar
  23. 23.
    Zou C, Sophie C, Stephane M, Elena M, Carmelo S, Yuan S, Song S, Zhu K, Dorostkar MM, Müller UC (2016) Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D-serine homeostasis. Embo J 35:2213–2222CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fanutza T, Del PD, Ford MJ, Castillo PE, D’Adamio L (2015) APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses. Elife Sci 4:e09743CrossRefGoogle Scholar
  25. 25.
    Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJS, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW (1995) Beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531CrossRefPubMedGoogle Scholar
  26. 26.
    Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu W-Y, MacDonald JF, Wang JY, Falls DL (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121–133CrossRefPubMedGoogle Scholar
  27. 27.
    Jia Z, Agopyan N, Miu P, Xiong Z, Henderson JT, Gerlai R, Taverna FA, Velumian AA, Macdonald JF, Carlen PL (1996) Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron 17:945–956CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou Z, Hu J, Passafaro M, Xie W, Jia Z (2011) GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. J Neurosci 31:819–833CrossRefPubMedGoogle Scholar
  29. 29.
    Liu A, Zhou Z, Dang R, Zhu Y, Qi J, He G, Leung C, Pak D, Jia Z, Xie W (2016) Neuroligin 1 regulates spines and synaptic plasticity via LIMK1/cofilin-mediated actin reorganization. J Cell Biol 212:449–463CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006) Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26:7212–7221CrossRefPubMedGoogle Scholar
  31. 31.
    Pyle JL, Kavalali ET, Piedras-Rentería ES, Tsien RW (2000) Rapid reuse of readily releasable pool vesicles at hippocampal synapses. Neuron 28:221–231CrossRefPubMedGoogle Scholar
  32. 32.
    Rizzoli SO and Betz WJ (2005) Synaptic vesicle pools. Nat Rev Neurosci 6:57–69CrossRefPubMedGoogle Scholar
  33. 33.
    Seabrook GR, Smith DW, Bowery BJ, Easter A, Reynolds T, Fitzjohn SM, Morton RA, Zheng H, Dawson GR, Sirinathsinghji DJ (1999) Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38:349–359CrossRefPubMedGoogle Scholar
  34. 34.
    Chi P, Greengard P, Ryan TA (2003) Synaptic vesicle mobilization is regulated by distinct synapsin i phosphorylation pathways at different frequencies. Neuron 38:69–78CrossRefPubMedGoogle Scholar
  35. 35.
    Esser L, Wang CR, Hosaka M, Smagula CS, Südhof TC, Deisenhofer J (1998) Synapsin I is structurally similar to ATP-utilizing enzymes. Embo J 17:977–984CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hosaka M, Südhof TC (1998) Synapsins I and II are ATP-binding proteins with differential Ca2+ regulation. J Biol Chem 273:1425–1429CrossRefPubMedGoogle Scholar
  37. 37.
    Song SH, Augustine GJ (2015) Synapsin Isoforms and Synaptic Vesicle Trafficking. Mol Cell 38:936–940CrossRefGoogle Scholar
  38. 38.
    Medrihan L, Cesca F, Raimondi A, Lignani G, Baldelli P, Benfenati F (2013) Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels. Nat Commun 4:1512CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Laßek M, Weingarten J, Einsfelder U, Brendel P, Müller U, Volknandt W (2013) Amyloid precursor proteins are constituents of the presynaptic active zone. J Neurochem 127:48–56PubMedGoogle Scholar
  40. 40.
    White RR, Kwon Y, Taing M, Lawrence DS, Edelman AM (1998) Definition of optimal substrate recognition motifs of Ca2+-calmodulin-dependent protein kinases IV and II reveals shared and distinctive features. J Biol Chem 273:3166–3172CrossRefPubMedGoogle Scholar
  41. 41.
    Leenders AGM, Sheng ZH (2005) Modulation of neurotransmitter release by the second messenger-activated protein kinases: implications for presynaptic plasticity. Pharmacol Ther 105:69–84CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yang L, Wang Z, Wang B, Justice NJ, Zheng H (2009) Amyloid precursor protein regulates Cav1.2 L type calcium channel levels and function to influence GABAergic short-term plasticity. J Neurosci 29:15660–15668CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kennedy MB, Greengard P (1981) Two calcium/calmodulin-dependent protein kinases, which are highly concentrated in brain, phosphorylate protein I at distinct sites. Proc Natl Acad Sci USA 78:1293-1297Google Scholar
  44. 44.
    Dolphin AC, Greengard P (1981) Neurotransmitter- and neuromodulator-dependent alterations in phosphorylation of protein I in slices of rat facial nucleus. J Neurosci 1:192–203CrossRefPubMedGoogle Scholar
  45. 45.
    Laßek M, Weingarten J, Ackerpalmer A, Bajjalieh SM, Muller U, Volknandt W (2014) Amyloid precursor protein knockout diminishes synaptic vesicle proteins at the presynaptic active zone in mouse brain. Curr Alzheimer Res 11:971CrossRefPubMedGoogle Scholar
  46. 46.
    Laßek M, Weingarten J, Wegner M, Mueller B, Rohmer M, Baeumlisberger D, Arrey TN, Hick M, Ackermann J, Ackerpalmer A (2016) APP Is a context-sensitive regulator of the hippocampal presynaptic active zone. PLoS Comput Biol 12:4CrossRefGoogle Scholar
  47. 47.
    Menegon A, Bonanomi D, Albertinazzi C, Lotti F, Ferrari G, Kao HT, Benfenati F, Baldelli P, Valtorta F (2006) Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2+-dependent synaptic activity. J Neurosci 26:11670–11681CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • An Liu
    • 1
  • Ying Zhang
    • 1
  • Lifang Han
    • 1
  • Guiqin He
    • 1
  • Wei Xie
    • 1
  • Zikai Zhou
    • 1
  • Zhengping Jia
    • 2
    • 3
    Email author
  1. 1.Institute of Life Sciences, The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of NeuroregenerationSoutheast UniversityNanjingChina
  2. 2.Neurosciences & Mental Healththe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Physiology, Faculty of MedicineUniversity of TorontoTorontoCanada

Personalised recommendations