Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • 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 8:1560–1567

    Article  PubMed  CAS  Google Scholar 

  • Both M, Bahner F, und Halbach O, Draguhn A (2008) Propagation of specific network patterns through the mouse hippocampus. Hippocampus 18:899–908

    Article  PubMed  Google Scholar 

  • 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 321:1686–1689

    Article  PubMed  CAS  Google Scholar 

  • Buzsaki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304:1926–1929

    Article  PubMed  CAS  Google Scholar 

  • Buzsaki G, Horvath Z, Urioste R, Hetke J, Wise K (1992) High-frequency network oscillation in the hippocampus. Science 256:1025–1027

    Article  PubMed  CAS  Google Scholar 

  • 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 35:183–193

    Article  PubMed  CAS  Google Scholar 

  • 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 19:274–287

    PubMed  CAS  Google Scholar 

  • 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 90:1–13

    Article  PubMed  CAS  Google Scholar 

  • 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 26:1280–1288

    Article  PubMed  Google Scholar 

  • Engel AK, Fries P, Singer W (2001) Dynamic predictions: oscillations and synchrony in top-down processing. Nat Rev Neurosci 2:704–716

    Article  PubMed  CAS  Google Scholar 

  • 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 288:9–12

    Article  PubMed  CAS  Google Scholar 

  • Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470

    Article  PubMed  CAS  Google Scholar 

  • 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 29:7582–7590

    Article  PubMed  CAS  Google Scholar 

  • Hebb DO (1949) The organization of behavior. Wiley, New York

    Google Scholar 

  • 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 20:7951–7963

    PubMed  CAS  Google Scholar 

  • 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 162:1081–1090

    Article  PubMed  CAS  Google Scholar 

  • 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 23:4106–4115

    Article  PubMed  CAS  Google Scholar 

  • 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 8:2133–2137

    Article  PubMed  CAS  Google Scholar 

  • King C, Henze DA, Leinekugel X, Buzsaki G (1999) Hebbian modification of a hippocampal population pattern in the rat. J Physiol 521(Pt 1):159–167

    Article  PubMed  CAS  Google Scholar 

  • Klausberger T, Somogyi P (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321:53–57

    Article  PubMed  CAS  Google Scholar 

  • Lanctot KL, Herrmann N, Rothenburg L, Eryavec G (2007) Behavioral correlates of GABAergic disruption in Alzheimer’s disease. Int Psychogeriatr 19:151–158

    Article  PubMed  Google Scholar 

  • Mann EO, Paulsen O (2007) Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci 30:343–349

    Article  PubMed  CAS  Google Scholar 

  • 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 1:345–347

    Article  PubMed  CAS  Google Scholar 

  • O’keefe J (1976) Place units in the hippocampus of the freely moving rat. Exp Neurol 51:78–109

    Article  PubMed  Google Scholar 

  • 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 26:7212–7220

    Article  PubMed  CAS  Google Scholar 

  • 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 28:14537–14545

    Article  PubMed  CAS  Google Scholar 

  • 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 69:819–830

    Article  PubMed  CAS  Google Scholar 

  • 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 27:7817–7826

    Article  PubMed  CAS  Google Scholar 

  • 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 26:2153–2163

    Article  PubMed  CAS  Google Scholar 

  • 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 38:349–359

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113

    Article  PubMed  CAS  Google Scholar 

  • 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 5:858–866

    Article  PubMed  CAS  Google Scholar 

  • 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 30:572–580

    Article  PubMed  CAS  Google Scholar 

  • 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 27:247–278

    Article  PubMed  CAS  Google Scholar 

  • 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 70:1–32

    Article  PubMed  CAS  Google Scholar 

  • Vanderwolf CH (1969) Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr Clin Neurophysiol 26:407–418

    Article  PubMed  CAS  Google Scholar 

  • 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 416:535–539

    Article  PubMed  CAS  Google Scholar 

  • 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 29:10788–10801

    Article  PubMed  CAS  Google Scholar 

  • 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 30:2266–2280

    Article  PubMed  CAS  Google Scholar 

  • Whittington MA, Traub RD (2003) Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26:676–682

    Article  PubMed  CAS  Google Scholar 

  • Wilson MA, McNaughton BL (1993) Dynamics of the hippocampal ensemble code for space. Science 261:1055–1058

    Article  PubMed  CAS  Google Scholar 

  • Wilson MA, McNaughton BL (1994) Reactivation of hippocampal ensemble memories during sleep. Science 265:676–679

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany

    Martin Korte & Ulrike Herrmann

  2. Institute for Physiology and Pathophysiology, Universität Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany

    Xiaomin Zhang & Andreas Draguhn

Authors
  1. Martin Korte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrike Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaomin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Draguhn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Korte.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Korte, M., Herrmann, U., Zhang, X. et al. The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models. Exp Brain Res 217, 435–440 (2012). https://doi.org/10.1007/s00221-011-2894-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-011-2894-6

Keywords

Search

Navigation