Experimental Brain Research

, Volume 217, Issue 3–4, pp 435–440 | Cite as

The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models

  • Martin Korte
  • Ulrike Herrmann
  • Xiaomin Zhang
  • Andreas Draguhn
Review

Abstract

APP, APLP1, and APLP2 form a family of mammalian membrane proteins with unknown function. APP, however, plays a key role in the molecular pathology of Alzheimer’s disease (AD), indicating that it is somehow involved in synaptic transmission, synaptic plasticity, memory formation, and maintenance of neurons. At present, most of our knowledge about the function of APP comes from consequences of AD-related mutations. The native role of APP, and even more of APLP1/2, remains largely unknown. New genetic knockout and knockin models involving several members of the APP/APLP family may yield better insight into the synaptic and systemic functions of these proteins. Here, we summarize recent results from such transgenic animals with special emphasis on synaptic plasticity and coherent patterns of memory-related network activity in the hippocampus. Data from APP knockout mice suggest that this protein is needed for the expression of long-term potentiation (LTP) in aged, but not in juvenile mice. The missing function can be rescued by expressing part of the protein, as well as by blocking inhibition. Double knockout mice lacking APP and APLP2 die shortly after birth indicating that different members of the APP/APLP family can mutually compensate for genetic ablation of single proteins. Recent techniques allow for analysis of tissue with combined defects, e.g., by expressing only part of APP in APLP2 knockout mice or by growing stem cells with multiple deletions on normal slice cultures. Data from these experiments confirm that APP and APLP2 do indeed play an important role in synaptic plasticity. Much less is known about the role of APP/APLP at the network level. Coherent patterns of activity like hippocampal network oscillations are believed to support formation and consolidation of memory. Analysis of such activity patterns in tissue from mice with altered expression of APP/APLP has just started and may shed further light on the importance of these proteins for cognitive functions.

Keywords

GABA Alzheimer’s disease Plasticity Network oscillations Spacial memory Dementia 

References

  1. Behrens CJ, van den Boom LP, de Hoz L, Friedman A, Heinemann U (2005) Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks. Nat Neurosci 8:1560–1567PubMedCrossRefGoogle Scholar
  2. Both M, Bahner F, und Halbach O, Draguhn A (2008) Propagation of specific network patterns through the mouse hippocampus. Hippocampus 18:899–908PubMedCrossRefGoogle Scholar
  3. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689PubMedCrossRefGoogle Scholar
  4. Buzsaki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304:1926–1929PubMedCrossRefGoogle Scholar
  5. Buzsaki G, Horvath Z, Urioste R, Hetke J, Wise K (1992) High-frequency network oscillation in the hippocampus. Science 256:1025–1027PubMedCrossRefGoogle Scholar
  6. Calabrese B, Shaked GM, Tabarean IV, Braga J, Koo EH, Halpain S (2007) Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol Cell Neurosci 35:183–193PubMedCrossRefGoogle Scholar
  7. Csicsvari J, Hirase H, Czurko A, Mamiya A, Buzsaki G (1999) Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving Rat. J Neurosci 19:274–287PubMedGoogle Scholar
  8. 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 90:1–13PubMedCrossRefGoogle Scholar
  9. Driver JE, Racca C, Cunningham MO, Towers SK, Davies CH, Whittington MA, LeBeau FE (2007) Impairment of hippocampal gamma-frequency oscillations in vitro in mice overexpressing human amyloid precursor protein (APP). Eur J Neurosci 26:1280–1288PubMedCrossRefGoogle Scholar
  10. Engel AK, Fries P, Singer W (2001) Dynamic predictions: oscillations and synchrony in top-down processing. Nat Rev Neurosci 2:704–716PubMedCrossRefGoogle Scholar
  11. Fitzjohn SM, Morton RA, Kuenzi F, Davies CH, Seabrook GR, Collingridge GL (2000) Similar levels of long-term potentiation in amyloid precursor protein -null and wild-type mice in the CA1 region of picrotoxin treated slices. Neurosci Lett 288:9–12PubMedCrossRefGoogle Scholar
  12. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470PubMedCrossRefGoogle Scholar
  13. Harmeier A, Wozny C, Rost BR, Munter LM, Huas H, Georgiev O, Beyermann M, Hildebrand PW, Weise C, Schaffner W, Schmitz D, Multhaup G (2009) Role of amyloid-ß glycine 33 in oligomerization, toxicity, and neuronal plasticity. J Neurosci 29:7582–7590PubMedCrossRefGoogle Scholar
  14. Hebb DO (1949) The organization of behavior. Wiley, New YorkGoogle Scholar
  15. 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 20:7951–7963PubMedGoogle Scholar
  16. Hermann D, Both M, Ebert U, Gross G, Schoemaker H, Draguhn A, Wicke K, Nimmrich V (2009) Synaptic transmission is impaired prior to plaque formation in amyloid precursor protein-overexpressing mice without altering behaviorally-correlated sharp wave-ripple complexes. Neuroscience 162:1081–1090PubMedCrossRefGoogle Scholar
  17. 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 23:4106–4115PubMedCrossRefGoogle Scholar
  18. 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 8:2133–2137PubMedCrossRefGoogle Scholar
  19. King C, Henze DA, Leinekugel X, Buzsaki G (1999) Hebbian modification of a hippocampal population pattern in the rat. J Physiol 521(Pt 1):159–167PubMedCrossRefGoogle Scholar
  20. Klausberger T, Somogyi P (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321:53–57PubMedCrossRefGoogle Scholar
  21. Lanctot KL, Herrmann N, Rothenburg L, Eryavec G (2007) Behavioral correlates of GABAergic disruption in Alzheimer’s disease. Int Psychogeriatr 19:151–158PubMedCrossRefGoogle Scholar
  22. Mann EO, Paulsen O (2007) Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci 30:343–349PubMedCrossRefGoogle Scholar
  23. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1:345–347PubMedCrossRefGoogle Scholar
  24. O’keefe J (1976) Place units in the hippocampus of the freely moving rat. Exp Neurol 51:78–109PubMedCrossRefGoogle Scholar
  25. 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 26:7212–7220PubMedCrossRefGoogle Scholar
  26. 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 28:14537–14545PubMedCrossRefGoogle Scholar
  27. Puzzo D, Privitera L, Fa’ M, Staniszewski A, Hashimoto G, Aziz F, Sakurai M, Ribe EM, Troy CM, Mercken M, Jung SS, Palmeri A, Arancio O (2011) Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 69:819–830PubMedCrossRefGoogle Scholar
  28. 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 27:7817–7826PubMedCrossRefGoogle Scholar
  29. Schrenk-Siemens K, Perez-Alcala S, Richter J, Lacroix E, Rahuel J, Korte M, Muller U, Barde YA, Bibel M (2008) Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. Stem Cells 26:2153–2163PubMedCrossRefGoogle Scholar
  30. 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 38:349–359PubMedCrossRefGoogle Scholar
  31. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedCrossRefGoogle Scholar
  32. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061PubMedCrossRefGoogle Scholar
  33. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113PubMedCrossRefGoogle Scholar
  34. Steinbach JP, Muller U, Leist M, Li ZW, Nicotera P, Aguzzi A (1998) Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. Cell Death Differ 5:858–866PubMedCrossRefGoogle Scholar
  35. 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 30:572–580PubMedCrossRefGoogle Scholar
  36. Traub RD, Bibbig A, LeBeau FE, Buhl EH, Whittington MA (2004) Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro. Annu Rev Neurosci 27:247–278PubMedCrossRefGoogle Scholar
  37. Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70:1–32PubMedCrossRefGoogle Scholar
  38. Vanderwolf CH (1969) Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr Clin Neurophysiol 26:407–418PubMedCrossRefGoogle Scholar
  39. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539PubMedCrossRefGoogle Scholar
  40. Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 29:10788–10801PubMedCrossRefGoogle Scholar
  41. 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 30:2266–2280PubMedCrossRefGoogle Scholar
  42. Whittington MA, Traub RD (2003) Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26:676–682PubMedCrossRefGoogle Scholar
  43. Wilson MA, McNaughton BL (1993) Dynamics of the hippocampal ensemble code for space. Science 261:1055–1058PubMedCrossRefGoogle Scholar
  44. Wilson MA, McNaughton BL (1994) Reactivation of hippocampal ensemble memories during sleep. Science 265:676–679PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Martin Korte
    • 1
  • Ulrike Herrmann
    • 1
  • Xiaomin Zhang
    • 2
  • Andreas Draguhn
    • 2
  1. 1.Division of Cellular NeurobiologyZoological Institute, TU BraunschweigBraunschweigGermany
  2. 2.Institute for Physiology and PathophysiologyUniversität HeidelbergHeidelbergGermany

Personalised recommendations