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Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

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An Erratum to this article was published on 20 December 2014

Abstract

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus-dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsα, but not APPsβ, indicating a crucial role for APPsα to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition.

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References

  1. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I (2009) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 12(12):1567–1576. doi:10.1038/nn.2433

    Article  CAS  PubMed  Google Scholar 

  2. Allinquant B, Hantraye P, Mailleux P, Moya K, Bouillot C, Prochiantz A (1995) Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. J Cell Biol 128(5):919–927

    Article  CAS  PubMed  Google Scholar 

  3. Anderson JJ, Holtz G, Baskin PP, Wang R, Mazzarelli L, Wagner SL, Menzaghi F (1999) Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits. Neuroscience 93(4):1409–1420. pii: S0306-4522(99)00244-4

    Article  CAS  PubMed  Google Scholar 

  4. Aydin D, Weyer SW, Muller UC (2012) Functions of the APP gene family in the nervous system: insights from mouse models. Exp Brain Res 217(3–4):423–434. doi:10.1007/s00221-011-2861-2

    Article  CAS  PubMed  Google Scholar 

  5. Bour A, Little S, Dodart JC, Kelche C, Mathis C (2004) A secreted form of the beta-amyloid precursor protein (sAPP695) improves spatial recognition memory in OF1 mice. Neurobiol Learn Mem 81(1):27–38. pii: S1074742703000716

    Article  CAS  PubMed  Google Scholar 

  6. Caldwell JH, Klevanski M, Saar M, Muller UC (2013) Roles of the amyloid precursor protein family in the peripheral nervous system. Mech Dev 130(6–8):433–446. doi:10.1016/j.mod.2012.11.001

    Article  CAS  PubMed  Google Scholar 

  7. Copanaki E, Chang S, Vlachos A, Tschape JA, Muller UC, Kogel D, Deller T (2010) sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress. Mol Cell Neurosci 44(4):386–393. doi:10.1016/j.mcn.2010.04.007

    Article  CAS  PubMed  Google Scholar 

  8. Cousins SL, Hoey SE, Anne Stephenson F, Perkinton MS (2009) Amyloid precursor protein 695 associates with assembled NR2A- and NR2B-containing NMDA receptors to result in the enhancement of their cell surface delivery. J Neurochem 111(6):1501–1513. doi:10.1111/j.1471-4159.2009.06424.x

    Article  CAS  PubMed  Google Scholar 

  9. Cousins SL, Innocent N, Stephenson FA (2013) Neto1 associates with the NMDA receptor/amyloid precursor protein complex. J Neurochem 126(5):554–564. doi:10.1111/jnc.12280

    Article  CAS  PubMed  Google Scholar 

  10. Crawley JN (2008) Behavioral phenotyping strategies for mutant mice. Neuron 57(6):809–818. doi:10.1016/j.neuron.2008.03.001

    Article  CAS  PubMed  Google Scholar 

  11. Dawson GR, Seabrook GR, Zheng H, Smith DW, Graham S, O’Dowd G, Bowery BJ, Boyce S, Trumbauer ME, Chen HY, Van der Ploeg LH, Sirinathsinghji DJ (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):1–13. pii: S0306-4522(98)00410-2

    Article  CAS  PubMed  Google Scholar 

  12. Deacon RM, Rawlins JN (2005) Hippocampal lesions, species-typical behaviours and anxiety in mice. Behav Brain Res 156(2):241–249. doi:10.1016/j.bbr.2004.05.027

    Article  PubMed  Google Scholar 

  13. Deyts C, Vetrivel KS, Das S, Shepherd YM, Dupre DJ, Thinakaran G, Parent AT (2012) Novel GalphaS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain. J Neurosci 32(5):1714–1729. doi:10.1523/JNEUROSCI.5433-11.2012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Dobrowolska JA, Kasten T, Huang Y, Benzinger TL, Sigurdson W, Ovod V, Morris JC, Bateman RJ (2014) Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One 9(3):e89998. doi:10.1371/journal.pone.0089998

    Article  PubMed Central  PubMed  Google Scholar 

  15. Endres K, Fahrenholz F (2012) Regulation of alpha-secretase ADAM10 expression and activity. Exp Brain Res 217(3–4):343–352. doi:10.1007/s00221-011-2885-7

    Article  CAS  PubMed  Google Scholar 

  16. Fazeli MS, Breen K, Errington ML, Bliss TV (1994) Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci Lett 169(1–2):77–80

    Article  CAS  PubMed  Google Scholar 

  17. Fogel H, Frere S, Segev O, Bharill S, Shapira I, Gazit N, O’Malley T, Slomowitz E, Berdichevsky Y, Walsh DM, Isacoff EY, Hirsch JA, Slutsky I (2014) APP homodimers transduce an amyloid-beta-mediated increase in release probability at excitatory synapses. Cell Rep 7(5):1560–1576. doi:10.1016/j.celrep.2014.04.024

    Article  CAS  PubMed  Google Scholar 

  18. Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67(5):1882–1896

    Article  CAS  PubMed  Google Scholar 

  19. Gakhar-Koppole N, Hundeshagen P, Mandl C, Weyer SW, Allinquant B, Muller U, Ciccolini F (2008) Activity requires soluble amyloid precursor protein alpha to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway. Eur J Neurosci 28(5):871–882. doi:10.1111/j.1460-9568.2008.06398.x

    Article  PubMed  Google Scholar 

  20. Goebbels S, Bormuth I, Bode U, Hermanson O, Schwab MH, Nave KA (2006) Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice. Genesis 44(12):611–621. doi:10.1002/dvg.20256

    Article  CAS  PubMed  Google Scholar 

  21. Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rulicke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Muller U (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20(21):7951–7963

    CAS  PubMed  Google Scholar 

  22. Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Muller U (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23(20):4106–4115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DT, Rebeck GW (2009) The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem 284(13):8495–8506. doi:10.1074/jbc.M900141200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Hoe HS, Lee HK, Pak DT (2012) The upside of APP at synapses. CNS Neurosci Ther 18(1):47–56. doi:10.1111/j.1755-5949.2010.00221.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Hoey SE, Williams RJ, Perkinton MS (2009) Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci 29(14):4442–4460. doi:10.1523/JNEUROSCI.6017-08.2009

    Article  CAS  PubMed  Google Scholar 

  26. Ishida A, Furukawa K, Keller JN, Mattson MP (1997) Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport 8(9–10):2133–2137

    Article  CAS  PubMed  Google Scholar 

  27. Jung CK, Herms J (2012) Role of APP for dendritic spine formation and stability. Exp Brain Res 217(3–4):463–470. doi:10.1007/s00221-011-2939-x

    Article  CAS  PubMed  Google Scholar 

  28. Klevanski M, Saar M, Baumkotter F, Weyer SW, Kins S, Muller UC (2014) Differential role of APP and APLPs for neuromuscular synaptic morphology and function. Mol Cell Neurosci 61C:201–210. doi:10.1016/j.mcn.2014.06.004

    Article  Google Scholar 

  29. Kogel D, Deller T, Behl C (2012) Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging. Exp Brain Res 217(3–4):471–479. doi:10.1007/s00221-011-2932-4

    Article  PubMed  Google Scholar 

  30. Lannfelt L, Basun H, Wahlund LO, Rowe BA, Wagner SL (1995) Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s disease. Nat Med 1(8):829–832

    Article  CAS  PubMed  Google Scholar 

  31. Lassek M, Weingarten J, Einsfelder U, Brendel P, Muller U, Volknandt W (2013) Amyloid precursor proteins are constituents of the presynaptic active zone. J Neurochem 127(1):48–56. doi:10.1111/jnc.12358

    CAS  PubMed  Google Scholar 

  32. 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(1):344–356. doi:10.1016/j.neuroscience.2010.04.078

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lichtenthaler SF, Haass C, Steiner H (2011) Regulated intramembrane proteolysis—lessons from amyloid precursor protein processing. J Neurochem 117(5):779–796. doi:10.1111/j.1471-4159.2011.07248.x

    Article  CAS  PubMed  Google Scholar 

  34. Lorent K, Overbergh L, Moechars D, De Strooper B, Van Leuven F, Van den Berghe H (1995) Expression in mouse embryos and in adult mouse brain of three members of the amyloid precursor protein family, of the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein and of its ligands apolipoprotein E, lipoprotein lipase, alpha-2-macroglobulin and the 40,000 molecular weight receptor-associated protein. Neuroscience 65(4):1009–1025

    Article  CAS  PubMed  Google Scholar 

  35. Magara F, Muller U, Li ZW, Lipp HP, Weissmann C, Stagljar M, Wolfer DP (1999) Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein. Proc Natl Acad Sci USA 96(8):4656–4661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Mallm JP, Tschape JA, Hick M, Filippov MA, Muller UC (2010) Generation of conditional null alleles for APP and APLP2. Genesis 48(3):200–206. doi:10.1002/dvg.20601

    CAS  PubMed  Google Scholar 

  37. Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R, Borroni B, Cattabeni F, Sala C, Padovani A, Di Luca M (2007) Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci 27(7):1682–1691. doi:10.1523/JNEUROSCI.3439-06.2007

    Article  CAS  PubMed  Google Scholar 

  38. Matrone C, Luvisetto S, La Rosa LR, Tamayev R, Pignataro A, Canu N, Yang L, Barbagallo AP, Biundo F, Lombino F, Zheng H, Ammassari-Teule M, D’Adamio L (2012) Tyr682 in the Abeta-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 11(6):1084–1093. doi:10.1111/acel.12009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci USA 95(21):12683–12688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Midthune B, Tyan SH, Walsh JJ, Sarsoza F, Eggert S, Hof PR, Dickstein DL, Koo EH (2012) Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Mol Cell Neurosci 49(4):448–455. doi:10.1016/j.mcn.2012.02.001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Milosch N, Tanriover G, Kundu A, Rami A, Francois JC, Baumkotter F, Weyer SW, Samanta A, Jaschke A, Brod F, Buchholz CJ, Kins S, Behl C, Muller UC, Kogel D (2014) Holo-APP and G-protein-mediated signaling are required for sAPPalpha-induced activation of the Akt survival pathway. Cell Death Dis 5:e1391. doi:10.1038/cddis.2014.352

    Article  CAS  PubMed  Google Scholar 

  42. Muller UC, Zheng H (2012) Physiological functions of APP family proteins. Cold Spring Harb Perspect Med 2(2):a006288. doi:10.1101/cshperspect.a006288

    Article  PubMed Central  PubMed  Google Scholar 

  43. Obregon D, Hou H, Deng J, Giunta B, Tian J, Darlington D, Shahaduzzaman M, Zhu Y, Mori T, Mattson MP, Tan J (2012) Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. Nat Commun 3:777. doi:10.1038/ncomms1781

    Article  PubMed Central  PubMed  Google Scholar 

  44. Priller C, Mitteregger G, Paluch S, Vassallo N, Staufenbiel M, Kretzschmar HA, Jucker M, Herms J (2009) Excitatory synaptic transmission is depressed in cultured hippocampal neurons of APP/PS1 mice. Neurobiol Aging 30(8):1227–1237. doi:10.1016/j.neurobiolaging.2007.10.016

    Article  CAS  PubMed  Google Scholar 

  45. Prox J, Bernreuther C, Altmeppen H, Grendel J, Glatzel M, D’Hooge R, Stroobants S, Ahmed T, Balschun D, Willem M, Lammich S, Isbrandt D, Schweizer M, Horre K, De Strooper B, Saftig P (2013) Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. J Neurosci 33(32):12915–12928. doi:10.1523/JNEUROSCI.5910-12.2013 (12928a)

    Article  CAS  PubMed  Google Scholar 

  46. Prox J, Rittger A, Saftig P (2012) Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin. Exp Brain Res 217(3–4):331–341. doi:10.1007/s00221-011-2952-0

    Article  CAS  PubMed  Google Scholar 

  47. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, Arancio O (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28(53):14537–14545. doi:10.1523/JNEUROSCI.2692-08.2008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M, Wolfer DP, Muller UC (2007) The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 27(29):7817–7826. doi:10.1523/JNEUROSCI.1026-07.2007

    Article  CAS  PubMed  Google Scholar 

  49. Seabrook GR, Smith DW, Bowery BJ, Easter A, Reynolds T, Fitzjohn SM, Morton RA, Zheng H, Dawson GR, Sirinathsinghji DJ, Davies CH, Collingridge GL, Hill RG (1999) Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38(3):349–359. pii: S0028390898002044

    Article  CAS  PubMed  Google Scholar 

  50. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. doi:10.1126/science.1074069

    Article  CAS  PubMed  Google Scholar 

  51. Soba P, Eggert S, Wagner K, Zentgraf H, Siehl K, Kreger S, Lower A, Langer A, Merdes G, Paro R, Masters CL, Muller U, Kins S, Beyreuther K (2005) Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J 24(20):3624–3634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Spires-Jones T, Knafo S (2012) Spines, plasticity, and cognition in Alzheimer’s model mice. Neural Plast 2012:319836. doi:10.1155/2012/319836

    PubMed Central  PubMed  Google Scholar 

  53. Steigerwald F, Schulz TW, Schenker LT, Kennedy MB, Seeburg PH, Kohr G (2000) C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J Neurosci 20(12):4573–4581

    CAS  PubMed  Google Scholar 

  54. Steiner P, Higley MJ, Xu W, Czervionke BL, Malenka RC, Sabatini BL (2008) Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron 60(5):788–802. doi:10.1016/j.neuron.2008.10.014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE (2013) ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80(2):385–401. doi:10.1016/j.neuron.2013.08.035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Taylor CJ, Ireland DR, Ballagh I, Bourne K, Marechal NM, Turner PR, Bilkey DK, Tate WP, Abraham WC (2008) Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol Dis 31(2):250–260. doi:10.1016/j.nbd.2008.04.011

    Article  CAS  PubMed  Google Scholar 

  57. 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(4):572–580. doi:10.1002/ana.410300410

    Article  CAS  PubMed  Google Scholar 

  58. 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 Cell Neurosci 51(1–2):43–52. doi:10.1016/j.mcn.2012.07.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, van der Ploeg LH, Price DL, Sisodia SS (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18(6):661–669

    Article  Google Scholar 

  60. Walsh DM, Minogue AM, Sala Frigerio C, Fadeeva JV, Wasco W, Selkoe DJ (2007) The APP family of proteins: similarities and differences. Biochem Soc Trans 35(Pt 2):416–420. doi:10.1042/BST0350416

    CAS  PubMed  Google Scholar 

  61. Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci 25(5):1219–1225

    Article  CAS  PubMed  Google Scholar 

  62. Weyer SW, Klevanski M, Delekate A, Voikar V, Aydin D, Hick M, Filippov M, Drost N, Schaller KL, Saar M, Vogt MA, Gass P, Samanta A, Jaschke A, Korte M, Wolfer DP, Caldwell JH, Muller UC (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30(11):2266–2280. doi:10.1038/emboj.2011.119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T, Muller UC (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsalpha expression. Acta Neuropathol Commun 2(1):36. doi:10.1186/2051-5960-2-36

    Article  PubMed Central  PubMed  Google Scholar 

  64. Wilhelm BG, Mandad S, Truckenbrodt S, Krohnert K, Schafer C, Rammner B, Koo SJ, Classen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344(6187):1023–1028. doi:10.1126/science.1252884

    Article  CAS  PubMed  Google Scholar 

  65. 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(50):15660–15668. doi:10.1523/JNEUROSCI.4104-09.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Young-Pearse TL, Chen AC, Chang R, Marquez C, Selkoe DJ (2008) Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev 3:15. doi:10.1186/1749-8104-3-15

    Article  PubMed Central  PubMed  Google Scholar 

  67. Zhang X, Herrmann U, Weyer SW, Both M, Muller UC, Korte M, Draguhn A (2013) Hippocampal network oscillations in APP/APLP2-deficient mice. PLoS One 8(4):e61198. doi:10.1371/journal.pone.0061198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We are grateful to Julia Gobbert, Michael Neumann, Claudia Meyer and Inger Drescher for excellent technical assistance. We thank Paul Mathews for kindly providing the M3.2 antibody and Klaus-Armin Nave for providing NexCre mice. We would also like to thank the Nikon Imaging Center (University of Heidelberg) for support with confocal microscopy and image analysis. This work was supported by the Deutsche Forschungsgemeinschaft Grants (MU 1457/8-1 and MU 1457/9-1, 9-2 to UM; KO 1674/3-1, 3-2 to MK; DR 326/7-1, 7-2 to AD), the ERA-Net Neuron (01EW1305A to UM) and the Breuer Stiftung (to UM). DPW is a member of the Zurich Center of Integrative Human Physiology ZIHP and the Neuroscience Center Zürich.

Conflict of interest

The authors declare no competing financial interests.

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Author notes

  1. Jan-Philipp Mallm

    Present address: Bioquant, Heidelberg University, Research Group Genome Organization & Function, Heidelberg, Germany

  2. Jakob-Andreas Tschäpe

    Present address: Roche Diagnostics International, Rotkreuz, Switzerland

Authors and Affiliations

  1. Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Meike Hick, Sascha W. Weyer, Jan-Philipp Mallm, Jakob-Andreas Tschäpe & Ulrike C. Müller

  2. Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany

    Ulrike Herrmann & Martin Korte

  3. Neuroscience Therapeutic Area, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Marianne Borgers & Marc Mercken

  4. Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

    Fabian C. Roth & Andreas Draguhn

  5. Institute of Anatomy, University of Zurich, Zurich, Switzerland

    Lutz Slomianka & David P. Wolfer

  6. Institute of Human Movement Sciences and Sport, ETH Zurich, Zurich, Switzerland

    David P. Wolfer

  7. AG NIND, HZI, Braunschweig, Germany

    Martin Korte

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M. Hick and U. Herrmann have equal contribution.

M. Korte and U. C. Müller shared senior authorship.

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Hick, M., Herrmann, U., Weyer, S.W. et al. Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity. Acta Neuropathol 129, 21–37 (2015). https://doi.org/10.1007/s00401-014-1368-x

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  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-014-1368-x

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