Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Not just amyloid: physiological functions of the amyloid precursor protein family

Key Points

  • Amyloid precursor protein (APP) and the APP-like proteins APLP1 and APLP2 form the mammalian APP gene family. They have important physiological functions in the peripheral and central nervous systems, some of which are still emerging.

  • APP family members share a similar structure and have partially overlapping functions. Their processing by canonical and non-canonical secretases results in numerous biologically active fragments, which mediate distinct and even opposing functions.

  • Membrane-bound APP family members interact in cis or in trans, which enables them to function as cell-adhesion molecules. Large numbers of extracellular and intracellular binding partners have been identified, and this Review summarizes those that are involved in physiological pathways in vivo.

  • Biological functions in which APP family members are involved include nervous system development, the formation and function of the neuromuscular junction, synaptogenesis, dendritic complexity and spine density, axonal growth and guidance, and synaptic functions, including synaptic plasticity, learning and memory.

  • α-Secretase cleavage of APP releases the neuroprotective and neurotrophic fragment APPsα. It upregulates protective pathways, inhibits neuronal apoptosis, increases neuronal resistance to brain injuries and has a crucial role in synaptic plasticity, learning and memory.

  • Increasing APPsα levels may be of therapeutic value. Pharmacotherapeutic and gene-therapeutic approaches could complement amyloid-targeting strategies.

Abstract

Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Schematic overview of APP-processing pathways.
Figure 2: Interactions and signalling modalities of APP family proteins.
Figure 3: APP and APP variants expressed in knock-in mice.

References

  1. Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).

    CAS  PubMed  Article  Google Scholar 

  2. Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235, 877–880 (1987).

    CAS  PubMed  Article  Google Scholar 

  3. Tanzi, R. E. et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884 (1987).

    CAS  PubMed  Article  Google Scholar 

  4. Habib, A., Sawmiller, D. & Tan, J. Restoring soluble amyloid precursor protein α functions as a potential treatment for Alzheimer's disease. J. Neurosci. Res. 95, 973–991 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. Obregon, D. et al. Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation. Nat. Commun. 3, 777 (2012).

    PubMed  Article  CAS  Google Scholar 

  6. Saftig, P. & Lichtenthaler, S. F. The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog. Neurobiol. 135, 1–20 (2015).

    CAS  PubMed  Article  Google Scholar 

  7. Shariati, S. A. & De Strooper, B. Redundancy and divergence in the amyloid precursor protein family. FEBS Lett. 587, 2036–2045 (2013).

    CAS  PubMed  Article  Google Scholar 

  8. Kuhn, P. H. et al. Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function. eLife 5, e12748 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  9. Kuhn, P. H. et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31, 3157–3168 (2012). This paper describes a novel proteomic approach known as SPECS to systematically identify and validate substrates of transmembrane proteases such as β-secretase 1.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Lichtenthaler, S. F., Haass, C. & Steiner, H. Regulated intramembrane proteolysis — lessons from amyloid precursor protein processing. J. Neurochem. 117, 779–796 (2011).

    CAS  PubMed  Article  Google Scholar 

  11. Muller, U. & Wild, K. Understanding Alzheimer's Disease (ed. Zerr, I.) (InTech, 2013).

    Google Scholar 

  12. Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement. 12, 733–748 (2016).

    PubMed  Article  Google Scholar 

  13. Morales-Corraliza, J. et al. In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the β-amyloid depositing mice. PLoS ONE 4, e7134 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Gralle, M. et al. Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein. J. Mol. Biol. 357, 493–508 (2006).

    CAS  PubMed  Article  Google Scholar 

  15. Peters-Libeu, C. et al. sAβPPα is a potent endogenous inhibitor of BACE1. J. Alzheimers Dis. 47, 545–555 (2015).

    CAS  PubMed  Article  Google Scholar 

  16. Ott, M. O. & Bullock, S. L. A gene trap insertion reveals that amyloid precursor protein expression is a very early event in murine embryogenesis. Dev. Genes Evol. 211, 355–357 (2001).

    CAS  PubMed  Article  Google Scholar 

  17. Sarasa, M. et al. Alzheimer β-amyloid precursor proteins display specific patterns of expression during embryogenesis. Mech. Dev. 94, 233–236 (2000).

    CAS  PubMed  Article  Google Scholar 

  18. Lorent, K. et al. 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, 1009–1025 (1995).

    CAS  PubMed  Article  Google Scholar 

  19. Salbaum, J. M. & Ruddle, F. H. Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. J. Exp. Zool. 269, 116–127 (1994).

    CAS  PubMed  Article  Google Scholar 

  20. Slunt, H. H. et al. Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP). J. Biol. Chem. 269, 2637–2644 (1994).

    CAS  PubMed  Google Scholar 

  21. Thinakaran, G. et al. Distribution of an APP homolog, APLP2, in the mouse olfactory system: a potential role for APLP2 in axogenesis. J. Neurosci. 15, 6314–6326 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Hick, M. et al. Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity. Acta Neuropathol. 129, 21–37 (2015). This study describes the role of APP and APLP2 in neuronal morphology, spine density, synaptic plasticity, learning and memory in the CNS using forebrain-specific App−/−Aplp2−/− mice.

    CAS  PubMed  Article  Google Scholar 

  23. Wang, B. et al. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J. Neurosci. 34, 13314–13325 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Haass, C., Hung, A. Y. & Selkoe, D. J. Processing of beta-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion. J. Neurosci. 11, 3783–3793 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. LeBlanc, A. C., Chen, H. Y., Autilio-Gambetti, L. & Gambetti, P. Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures. FEBS Lett. 292, 171–178 (1991).

    CAS  PubMed  Article  Google Scholar 

  26. Guo, Q. et al. Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives. J. Biol. Chem. 287, 2437–2445 (2012).

    CAS  PubMed  Article  Google Scholar 

  27. Szodorai, A. et al. APP anterograde transport requires Rab3A GTPase activity for assembly of the transport vesicle. J. Neurosci. 29, 14534–14544 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Groemer, T. W. et al. Amyloid precursor protein is trafficked and secreted via synaptic vesicles. PLoS ONE 6, e18754 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Lassek, M. et al. Amyloid precursor proteins are constituents of the presynaptic active zone. J. Neurochem. 127, 48–56 (2013).

    CAS  PubMed  Google Scholar 

  30. Wilhelm, B. G. et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344, 1023–1028 (2014).

    CAS  PubMed  Article  Google Scholar 

  31. DeBoer, S. R., Dolios, G., Wang, R. & Sisodia, S. S. Differential release of β-amyloid from dendrite-versus axon-targeted APP. J. Neurosci. 34, 12313–12327 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Yamazaki, T., Selkoe, D. J. & Koo, E. H. Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J. Cell Biol. 129, 431–442 (1995).

    CAS  PubMed  Article  Google Scholar 

  33. Jiang, S. et al. Trafficking regulation of proteins in Alzheimer's disease. Mol. Neurodegener. 9, 6 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Kaden, D. et al. Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2. J. Cell Sci. 122, 368–377 (2009).

    CAS  PubMed  Article  Google Scholar 

  35. Sannerud, R. et al. ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc. Natl Acad. Sci. USA 108, E559–E568 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Das, U. et al. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79, 447–460 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Das, U. et al. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat. Neurosci. 19, 55–64 (2016).

    CAS  PubMed  Article  Google Scholar 

  38. van der Kant, R. & Goldstein, L. S. Cellular functions of the amyloid precursor protein from development to dementia. Dev. Cell 32, 502–515 (2015).

    CAS  PubMed  Article  Google Scholar 

  39. Vassar, R. et al. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J. Neurochem. 130, 4–28 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Hoe, H. S., Lee, H. K. & Pak, D. T. The upside of APP at synapses. CNS Neurosci. Ther. 18, 47–56 (2012).

    CAS  PubMed  Article  Google Scholar 

  41. Hoey, S. E., Williams, R. J. & Perkinton, M. S. Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production. J. Neurosci. 29, 4442–4460 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Prox, J. et al. Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. J. Neurosci. 33, 12915–12928 (2013). This study describes the phenotype of mice with a conditional knockout of ADAM10 in postnatal forebrain neurons, and by this means confirmed ADAM10 as the major α-secretase and highlighted several other substrates that are affected in addition to APP.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Kuhn, P. H. et al. ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29, 3020–3032 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Tomita, T. Molecular mechanism of intramembrane proteolysis by γ-secretase. J. Biochem. 156, 195–201 (2014).

    CAS  PubMed  Article  Google Scholar 

  45. Eggert, S. et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ɛ-like cleavages: modulation of APLP-1 processing by N-glycosylation. J. Biol. Chem. 279, 18146–18156 (2004).

    CAS  PubMed  Article  Google Scholar 

  46. Scheinfeld, M. H., Ghersi, E., Laky, K., Fowlkes, B. J. & D'Adamio, L. Processing of β-amyloid precursor-like protein-1 and -2 by γ-secretase regulates transcription. J. Biol. Chem. 277, 44195–44201 (2002).

    CAS  PubMed  Article  Google Scholar 

  47. Endres, K., Postina, R., Schroeder, A., Mueller, U. & Fahrenholz, F. Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. FEBS J. 272, 5808–5820 (2005).

    CAS  PubMed  Article  Google Scholar 

  48. Willem, M. et al. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526, 443–447 (2015). This study identifies a novel processing pathway for APP that leads to the generation of fragments arising by combined cleavage of η-secretase and either α-secretase or β-secretase.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Nhan, H. S., Chiang, K. & Koo, E. H. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol. 129, 1–19 (2015).

    CAS  PubMed  Article  Google Scholar 

  50. Fanutza, T., Del Prete, D., Ford, M. J., Castillo, P. E. & D'Adamio, L. APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses. eLife 4, e09743 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  51. Andrew, R. J., Kellett, K. A. B., Thinkaran, G. & Hooper, N. M. A Greek tragedy: the growing complexity of Alzheimer amyloid precursor protein proteolysis. J. Biol. Chem. 291, 19235–19344 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Zhang, Z. et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease. Nat. Commun. 6, 8762 (2015).

    CAS  PubMed  Article  Google Scholar 

  53. Jefferson, T. et al. Metalloprotease meprin β generates nontoxic N-terminal amyloid precursor protein fragments in vivo. J. Biol. Chem. 286, 27741–27750 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Dahms, S. O. et al. Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc. Natl Acad. Sci. USA 107, 5381–5386 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. Xue, Y., Lee, S. & Ha, Y. Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization. Proc. Natl Acad. Sci. USA 108, 16229–16234 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. Soba, P. et al. Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J. 24, 3624–3634 (2005). This study shows the functional importance of trans dimerization of APP family proteins, which is the basis for their properties as synaptic adhesion molecules.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Munter, L. M. et al. GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42. EMBO J. 26, 1702–1712 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Baumkötter, F. et al. Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain. J. Neurosci. 34, 11159–11172 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. Wang, Z. et al. Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J. Neurosci. 29, 10788–10801 (2009). This study indicates that APP is required at both the presynaptic and the postsynaptic site at the NMJ and functions as a trans-synaptic adhesion molecule.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Muller, U. C. & Zheng, H. Physiological functions of APP family proteins. Cold Spring Harb. Perspect. Med. 2, a006288 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. Stahl, R. et al. Shedding of APP limits its synaptogenic activity and cell adhesion properties. Front. Cell. Neurosci. 8, 410 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  62. Milosch, N. et al. Holo-APP and G-protein-mediated signaling are required for sAPPα-induced activation of the Akt survival pathway. Cell Death Dis. 5, e1391 (2014). This study indicates that APPsα binds as a ligand to APP and triggers a G protein-mediated signalling cascade that is important for cell survival.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Deyts, C., Thinakaran, G. & Parent, A. T. APP receptor? To be or not to be. Trends Pharmacol. Sci. 37, 390–411 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Perreau, V. M. et al. A domain level interaction network of amyloid precursor protein and Aβ of Alzheimer's disease. Proteomics 10, 2377–2395 (2010).

    CAS  PubMed  Article  Google Scholar 

  65. Matsuda, S. et al. The familial dementia BRI2 gene binds the Alzheimer gene amyloid-β precursor protein and inhibits amyloid-β production. J. Biol. Chem. 280, 28912–28916 (2005).

    CAS  PubMed  Article  Google Scholar 

  66. Matsuda, S., Matsuda, Y. & D'Adamio, L. BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. J. Biol. Chem. 284, 15815–15825 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Tamayev, R., Matsuda, S., Arancio, O. & D'Adamio, L. β-but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol. Med. 4, 171–179 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Tamayev, R., Zhou, D. & D'Adamio, L. The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol. Neurodegener. 4, 28 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. Deyts, C. et al. Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain. J. Neurosci. 32, 1714–1729 (2012). This is the first study to show a functional role for APP signalling as an unconventional G protein-coupled receptor.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Deyts, C. et al. Loss of presenilin function is associated with a selective gain of APP function. eLife 5, e15645 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  71. Weyer, S. W. et al. APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J. 30, 2266–2280 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Norstrom, E. M., Zhang, C., Tanzi, R. & Sisodia, S. S. Identification of NEEP21 as a β-amyloid precursor protein-interacting protein in vivo that modulates amyloidogenic processing in vitro. J. Neurosci. 30, 15677–15685 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Kohli, B. M. et al. Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. J. Proteome Res. 11, 4075–4090 (2012).

    CAS  PubMed  Article  Google Scholar 

  74. Cousins, S. L., Dai, W. & Stephenson, F. A. APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression. J. Neurochem. 133, 879–885 (2015).

    CAS  PubMed  Article  Google Scholar 

  75. Cousins, S. L., Hoey, S. E., Anne Stephenson, F. & Perkinton, M. S. 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, 1501–1513 (2009).

    CAS  PubMed  Article  Google Scholar 

  76. Cousins, S. L., Innocent, N. & Stephenson, F. A. Neto1 associates with the NMDA receptor/amyloid precursor protein complex. J. Neurochem. 126, 554–564 (2013).

    CAS  PubMed  Article  Google Scholar 

  77. Hoe, H. S. et al. The effects of amyloid precursor protein on postsynaptic composition and activity. J. Biol. Chem. 284, 8495–8506 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Cao, X. & Sudhof, T. C. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120 (2001).

    CAS  PubMed  Article  Google Scholar 

  79. Konietzko, U. AICD nuclear signaling and its possible contribution to Alzheimer's disease. Curr. Alzheimer Res. 9, 200–216 (2012).

    CAS  PubMed  Article  Google Scholar 

  80. Choi, H. Y. et al. APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. eLife 2, e00220 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  81. Osterhout, J. A., Stafford, B. K., Nguyen, P. L., Yoshihara, Y. & Huberman, A. D. Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron 86, 985–999 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Olsen, O. et al. 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, 6438–6447 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Xu, K., Olsen, O., Tzvetkova-Robev, D., Tessier-Lavigne, M. & Nikolov, D. B. The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Genes Dev. 29, 785–790 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Marik, S. A., Olsen, O., Tessier-Lavigne, M. & Gilbert, C. D. Physiological role for amyloid precursor protein in adult experience-dependent plasticity. Proc. Natl Acad. Sci. USA 113, 7912–7917 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. Nikolaev, A., McLaughlin, T., O'Leary, D. D. & Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Strilic, B. et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536, 215–218 (2016).

    CAS  Article  PubMed  Google Scholar 

  87. Kallop, D. Y. et al. A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer's disease-related pathophysiology in murine models. J. Neurosci. 34, 6425–6437 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V. & Hooper, N. M. Amyloid-β receptors: the good, the bad, and the prion protein. J. Biol. Chem. 291, 3174–3183 (2016).

    CAS  PubMed  Article  Google Scholar 

  89. Zheng, H. et al. β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531 (1995).

    CAS  PubMed  Article  Google Scholar 

  90. Li, Z. W. et al. Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells. Proc. Natl Acad. Sci. USA 93, 6158–6162 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. Ring, S. et al. 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, 7817–7826 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Steinbach, J. P. et al. Hypersensitivity to seizures in β-amyloid precursor protein deficient mice. Cell Death Differ. 5, 858–866 (1998).

    CAS  PubMed  Article  Google Scholar 

  93. Hefter, D. et al. Amyloid precursor protein protects neuronal network function after hypoxia via control of voltage-gated calcium channels. J. Neurosci. 36, 8356–8371 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Corrigan, F. et al. sAPPα rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury. J. Neurochem. 122, 208–220 (2012). This study demonstrates the in vivo importance of APPsα in neuroprotection in a model of acute brain lesioning.

    CAS  PubMed  Article  Google Scholar 

  95. Dawson, G. R. et al. Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein. Neuroscience 90, 1–13 (1999). This is the first study to show that the loss of APP leads to deficits in cognition and synaptic plasticity.

    CAS  PubMed  Article  Google Scholar 

  96. Seabrook, G. R. et al. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38, 349–359 (1999).

    CAS  PubMed  Article  Google Scholar 

  97. Tyan, S. H. et al. Amyloid precursor protein (APP) regulates synaptic structure and function. Mol. Cell. Neurosci. 51, 43–52 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Zou, C. et al. Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating d-serine homeostasis. EMBO J. 35, 2213–2222 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Lee, K. J. et al. Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines. Neuroscience 169, 344–356 (2010).

    CAS  PubMed  Article  Google Scholar 

  100. Heber, S. et al. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20, 7951–7963 (2000). This study describes the generation of APLP1-deficient mice and all three possible combinations of double knockouts, highlighting the crucial physiological role of APLP2 for postnatal survival.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. Dinet, V. et al. Amyloid precursor-like protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics. Mol. Brain 9, 64 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. von Koch, C. S. et al. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol. Aging 18, 661–669 (1997).

    CAS  PubMed  Article  Google Scholar 

  103. Herms, J. et al. Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 23, 4106–4115 (2004). This paper describes the generation of constitutive triple-knockout mice and shows the importance of APP family proteins in cortical development.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Wang, P. et al. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J. Neurosci. 25, 1219–1225 (2005). This is the first study to indicate that APP and APLP2 are crucial for proper NMJ formation and transmitter release.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Klevanski, M. et al. Differential role of APP and APLPs for neuromuscular synaptic morphology and function. Mol. Cell. Neurosci. 61, 201–210 (2014).

    CAS  PubMed  Article  Google Scholar 

  106. Yang, L., Wang, B., Long, C., Wu, G. & Zheng, H. Increased asynchronous release and aberrant calcium channel activation in amyloid precursor protein deficient neuromuscular synapses. Neuroscience 149, 768–778 (2007).

    CAS  PubMed  Article  Google Scholar 

  107. Lopez-Sanchez, N., Muller, U. & Frade, J. M. Lengthening of G2/mitosis in cortical precursors from mice lacking β-amyloid precursor protein. Neuroscience 130, 51–60 (2005).

    CAS  PubMed  Article  Google Scholar 

  108. Ma, Q. H. et al. A TAG1–APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat. Cell Biol. 10, 283–294 (2008).

    CAS  PubMed  Article  Google Scholar 

  109. Magara, F. et al. Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the β-amyloid-precursor protein. Proc. Natl Acad. Sci. USA 96, 4656–4661 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. Guenette, S. et al. Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development. EMBO J. 25, 420–431 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Shariati, S. A. et al. APLP2 regulates neuronal stem cell differentiation during cortical development. J. Cell Sci. 126, 1268–1277 (2013).

    CAS  PubMed  Article  Google Scholar 

  112. Young-Pearse, T. L. et al. A critical function for β-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J. Neurosci. 27, 14459–14469 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Rice, H. C. et al. Pancortins interact with amyloid precursor protein and modulate cortical cell migration. Development 139, 3986–3996 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Sabo, S. L., Ikin, A. F., Buxbaum, J. D. & Greengard, P. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo. J. Neurosci. 23, 5407–5415 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Cheung, H. N. et al. FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth. FASEB J. 28, 337–349 (2014).

    CAS  PubMed  Article  Google Scholar 

  116. Rama, N. et al. Amyloid precursor protein regulates netrin-1-mediated commissural axon outgrowth. J. Biol. Chem. 287, 30014–30023 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Sosa, L. J. et al. Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance. PLoS ONE 8, e64521 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Young-Pearse, T. L., Chen, A. C., Chang, R., Marquez, C. & Selkoe, D. J. Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin β1. Neural Dev. 3, 15 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. Caldwell, J. H., Klevanski, M., Saar, M. & Muller, U. C. Roles of the amyloid precursor protein family in the peripheral nervous system. Mech. Dev. 130, 433–446 (2013).

    CAS  PubMed  Article  Google Scholar 

  120. Wang, B., Yang, L., Wang, Z. & Zheng, H. Amyloid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc. Natl Acad. Sci. USA 104, 14140–14145 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. Yang, G. et al. Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci. Lett. 384, 66–71 (2005).

    CAS  PubMed  Article  Google Scholar 

  122. Klevanski, M. et al. The APP intracellular domain is required for normal synaptic morphology, synaptic plasticity, and hippocampus-dependent behavior. J. Neurosci. 35, 16018–16033 (2015). This study indicates that mice lacking APLP2 and the APP C terminus are partially viable and produce drastically reduced Aβ, and indicated that, in addition to APPsα, transmembrane APP isoforms are also important for normal CNS function.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Li, H. et al. Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis. J. Biol. Chem. 285, 30598–30605 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Barbagallo, A. P., Wang, Z., Zheng, H. & D'Adamio, L. The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. PLoS ONE 6, e18006 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Barbagallo, A. P., Wang, Z., Zheng, H. & D'Adamio, L. A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J. Biol. Chem. 286, 8717–8721 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Li, H. et al. Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc. Natl Acad. Sci. USA 107, 17362–17367 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. Weyer, S. W. et al. 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, 36 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  128. Perez, R. G., Zheng, H., Van der Ploeg, L. H. & Koo, E. H. The β-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity. J. Neurosci. 17, 9407–9414 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. Matrone, C. et al. Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 11, 1084–1093 (2012).

    CAS  PubMed  Article  Google Scholar 

  130. Midthune, B. et al. Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Mol. Cell. Neurosci. 49, 448–455 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Bittner, T. et al. γ-Secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J. Neurosci. 29, 10405–10409 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Fol, R. et al. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer's disease mouse model. Acta Neuropathol. 131, 247–266 (2016). This paper indicates the therapeutic potential of APPsα expressed in the brain of aged transgenic APP/PS1 mice.

    CAS  PubMed  Article  Google Scholar 

  133. Panatier, A. et al. Glia-derived d-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    CAS  PubMed  Article  Google Scholar 

  134. Ultanir, S. K. et al. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo. Proc. Natl Acad. Sci. USA 104, 19553–19558 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. Korte, M. & Schmitz, D. Cellular and system biology of memory: timing, molecules, and beyond. Physiol. Rev. 96, 647–693 (2016).

    CAS  PubMed  Article  Google Scholar 

  136. Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    CAS  Article  PubMed  Google Scholar 

  137. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. De Strooper, B. & Karran, E. The cellular phase of Alzheimer's disease. Cell 164, 603–615 (2016).

    CAS  PubMed  Article  Google Scholar 

  139. Vnencak, M. et al. Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus. J. Comp. Neurol. 523, 1717–1729 (2015).

    CAS  PubMed  Article  Google Scholar 

  140. Stevens, C. F. & Wesseling, J. F. Augmentation is a potentiation of the exocytotic process. Neuron 22, 139–146 (1999).

    CAS  PubMed  Article  Google Scholar 

  141. Ishida, A., Furukawa, K., Keller, J. N. & Mattson, M. P. Secreted form of β-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport 8, 2133–2137 (1997).

    CAS  PubMed  Article  Google Scholar 

  142. Meziane, H. et al. Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice. Proc. Natl Acad. Sci. USA 95, 12683–12688 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. Mileusnic, R., Lancashire, C. L., Johnston, A. N. & Rose, S. P. APP is required during an early phase of memory formation. Eur. J. Neurosci. 12, 4487–4495 (2000).

    CAS  PubMed  Google Scholar 

  144. Mileusnic, R., Lancashire, C. L. & Rose, S. P. The peptide sequence Arg-Glu-Arg, present in the amyloid precursor protein, protects against memory loss caused by Aβ and acts as a cognitive enhancer. Eur. J. Neurosci. 19, 1933–1938 (2004).

    CAS  PubMed  Article  Google Scholar 

  145. Roch, J. M. et al. Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid β/A4 protein precursor. Proc. Natl Acad. Sci. USA 91, 7450–7454 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. Gakhar-Koppole, N. et al. Activity requires soluble amyloid precursor protein α to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway. Eur. J. Neurosci. 28, 871–882 (2008).

    PubMed  Article  Google Scholar 

  147. Mills, J. & Reiner, P. B. Mitogen-activated protein kinase is involved in N-methyl-d-aspartate receptor regulation of amyloid precursor protein cleavage. Neuroscience 94, 1333–1338 (1999).

    CAS  PubMed  Article  Google Scholar 

  148. Fazeli, M. S., Breen, K., Errington, M. L. & Bliss, T. V. Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci. Lett. 169, 77–80 (1994).

    CAS  PubMed  Article  Google Scholar 

  149. Nitsch, R. M. et al. Muscarinic acetylcholine receptors activate the acetylcholinesterase gene promoter. J. Physiol. Paris 92, 257–264 (1998).

    CAS  PubMed  Article  Google Scholar 

  150. Nitsch, R. M., Slack, B. E., Wurtman, R. J. & Growdon, J. H. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304–307 (1992).

    CAS  PubMed  Article  Google Scholar 

  151. Taylor, C. J. et al. Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol. Dis. 31, 250–260 (2008). This study shows the importance of endogenous APPsα for synaptic plasticity in vivo using intrahippocampal infusion of antibodies, α-secretase inhibitors and reconstitution with recombinant APPsα.

    CAS  PubMed  Article  Google Scholar 

  152. Anderson, J. J. et al. Reduced cerebrospinal fluid levels of α-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits. Neuroscience 93, 1409–1420 (1999).

    CAS  PubMed  Article  Google Scholar 

  153. Moreno, L. et al. sAβPPα improves hippocampal NMDA-dependent functional alterations linked to healthy aging. J. Alzheimers Dis. 48, 927–935 (2015).

    CAS  PubMed  Article  Google Scholar 

  154. Xiong, M. et al. Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats. Neurobiol. Learn. Mem. http://dx.doi.org/10.1016/j.nlm.2016.08.002 (2016).

  155. Claasen, A. M. et al. Secreted amyloid precursor protein-α upregulates synaptic protein synthesis by a protein kinase G-dependent mechanism. Neurosci. Lett. 460, 92–96 (2009).

    CAS  PubMed  Article  Google Scholar 

  156. Stein, T. D. et al. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J. Neurosci. 24, 7707–7717 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Ryan, M. M. et al. Time-dependent changes in gene expression induced by secreted amyloid precursor protein-alpha in the rat hippocampus. BMC Genomics 14, 376 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Aydin, D. et al. Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex. BMC Genomics 12, 160 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Strecker, P. et al. FE65 and FE65L1 share common synaptic functions and genetically interact with the APP family in neuromuscular junction formation. Sci. Rep. 6, 25652 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. Kogel, D., Deller, T. & Behl, C. Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging. Exp. Brain Res. 217, 471–479 (2012).

    PubMed  Article  CAS  Google Scholar 

  161. Szczygielski, J. et al. Traumatic brain injury: cause or risk of Alzheimer's disease? A review of experimental studies. J. Neural Transm. (Vienna) 112, 1547–1564 (2005).

    CAS  Article  Google Scholar 

  162. Plummer, S., Van den Heuvel, C., Thornton, E., Corrigan, F. & Cappai, R. The neuroprotective properties of the amyloid precursor protein following traumatic brain injury. Aging Dis. 7, 163–179 (2016). This is an interesting review on the role of APP in TBI.

    PubMed  PubMed Central  Article  Google Scholar 

  163. Lu, K. P. et al. Potential of the antibody against cis-phosphorylated tau in the early diagnosis, treatment, and prevention of Alzheimer disease and brain injury. JAMA Neurol. 73, 1356–1362 (2016).

    PubMed  Article  Google Scholar 

  164. Van den Heuvel, C. et al. Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp. Neurol. 159, 441–450 (1999).

    CAS  PubMed  Article  Google Scholar 

  165. Thornton, E., Vink, R., Blumbergs, P. C. & Van Den Heuvel, C. Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res. 1094, 38–46 (2006).

    CAS  PubMed  Article  Google Scholar 

  166. Corrigan, F. et al. The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96–110. J. Neurochem. 128, 196–204 (2014).

    CAS  PubMed  Article  Google Scholar 

  167. Del Turco, D., Schlaudraff, J., Bonin, M. & Deller, T. Upregulation of APP, ADAM10 and ADAM17 in the denervated mouse dentate gyrus. PLoS ONE 9, e84962 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. Cheng, G., Yu, Z., Zhou, D. & Mattson, M. P. Phosphatidylinositol-3-kinase-Akt kinase and p42/p44 mitogen-activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein. Exp. Neurol. 175, 407–414 (2002).

    CAS  PubMed  Article  Google Scholar 

  169. Guo, Q., Robinson, N. & Mattson, M. P. Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF- κB and stabilization of calcium homeostasis. J. Biol. Chem. 273, 12341–12351 (1998).

    CAS  PubMed  Article  Google Scholar 

  170. Greenberg, S. M. & Kosik, K. S. Secreted β-APP stimulates MAP kinase and phosphorylation of tau in neurons. Neurobiol. Aging 16, 403–407 (1995).

    CAS  PubMed  Article  Google Scholar 

  171. Gralle, M., Botelho, M. G. & Wouters, F. S. Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers. J. Biol. Chem. 284, 15016–15025 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. Vilchez, D., Saez, I. & Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5, 5659 (2014).

    CAS  Article  PubMed  Google Scholar 

  173. Gentier, R. J. & van Leeuwen, F. W. Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease. Front. Mol. Neurosci. 8, 47 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. Kundu, A. et al. Modulation of BAG3 expression and proteasomal activity by sAPPα does not require membrane-tethered holo-APP. Mol. Neurobiol. 53, 5985–5994 (2015).

    PubMed  Article  CAS  Google Scholar 

  175. Colciaghi, F. et al. α-Secretase ADAM10 as well as αAPPs is reduced in platelets and CSF of Alzheimer disease patients. Mol. Med. 8, 67–74 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Furukawa, K. & Mattson, M. P. Secreted amyloid precursor protein alpha selectively suppresses N-methyl-d-aspartate currents in hippocampal neurons: involvement of cyclic GMP. Neuroscience 83, 429–438 (1998).

    CAS  PubMed  Article  Google Scholar 

  177. Mattson, M. P. et al. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10, 243–254 (1993).

    CAS  PubMed  Article  Google Scholar 

  178. Rossjohn, J. et al. Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat. Struct. Biol. 6, 327–331 (1999).

    CAS  PubMed  Article  Google Scholar 

  179. Ninomiya, H., Roch, J. M., Sundsmo, M. P., Otero, D. A. & Saitoh, T. Amino acid sequence RERMS represents the active domain of amyloid beta/A4 protein precursor that promotes fibroblast growth. J. Cell Biol. 121, 879–886 (1993).

    CAS  PubMed  Article  Google Scholar 

  180. Roch, J. M., Jin, L. W., Ninomiya, H., Schubert, D. & Saitoh, T. Biologically active domain of the secreted form of the amyloid β/A4 protein precursor. Ann. NY Acad. Sci. 695, 149–157 (1993).

    CAS  PubMed  Article  Google Scholar 

  181. Dawkins, E. & Small, D. H. Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease. J. Neurochem. 129, 756–769 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Duce, J. A. et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857–867 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. Multhaup, G. et al. The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I). Science 271, 1406–1409 (1996).

    CAS  PubMed  Article  Google Scholar 

  184. Yan, R. & Vassar, R. Targeting the β secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 13, 319–329 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. Geldenhuys, W. J. & Darvesh, A. S. Pharmacotherapy of Alzheimer's disease: current and future trends. Expert Rev. Neurother. 15, 3–5 (2015).

    CAS  PubMed  Article  Google Scholar 

  186. Netzer, W. J. et al. Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage. Proc. Natl Acad. Sci. USA 114, 1389–1394 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. Golde, T. E. Overcoming translational barriers impeding development of Alzheimer's disease modifying therapies. J. Neurochem. 139 (Suppl. 2), 224–236 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  188. Endres, K. & Fahrenholz, F. Regulation of α-secretase ADAM10 expression and activity. Exp. Brain Res. 217, 343–352 (2012).

    CAS  PubMed  Article  Google Scholar 

  189. Siopi, E. et al. Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice. Neuropharmacology 67, 183–192 (2013).

    CAS  PubMed  Article  Google Scholar 

  190. Endres, K. et al. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology 83, 1930–1935 (2014).

    CAS  PubMed  Article  Google Scholar 

  191. Hocquemiller, M., Giersch, L., Audrain, M., Parker, S. & Cartier, N. Adeno-associated virus-based gene therapy for CNS diseases. Hum. Gene Ther. 27, 478–496 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. Tuszynski, M. H. et al. Nerve growth factor gene therapy: activation of neuronal responses in Alzheimer disease. JAMA Neurol. 72, 1139–1147 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  193. Barbagallo, A. P. et al. Tyr682 in the intracellular domain of APP regulates amyloidogenic APP processing in vivo. PLoS ONE 5, e15503 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. White, A. R. et al. Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res. 842, 439–444 (1999).

    CAS  PubMed  Article  Google Scholar 

  195. Grimm, M. O. et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nat. Cell Biol. 7, 1118–1123 (2005).

    CAS  PubMed  Article  Google Scholar 

  196. Caille, I. et al. Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development 131, 2173–2181 (2004).

    CAS  PubMed  Article  Google Scholar 

  197. Jedlicka, P. et al. Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo. Exp. Brain Res. 217, 441–447 (2012).

    CAS  PubMed  Article  Google Scholar 

  198. Yang, L., Wang, Z., Wang, B., Justice, N. J. & Zheng, H. Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J. Neurosci. 29, 15660–15668 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. Deng, J. et al. Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway. J. Neurochem. 135, 630–637 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. Smith-Swintosky, V. L. et al. Secreted forms of β-amyloid precursor protein protect against ischemic brain injury. J. Neurochem. 63, 781–784 (1994).

    CAS  PubMed  Article  Google Scholar 

  201. Bailey, A. R. et al. GFAP expression and social deficits in transgenic mice overexpressing human sAPPα. Glia 61, 1556–1569 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  202. Puzzo, D. et al. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann. Neurol. 69, 819–830 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. Puzzo, D. et al. Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 28, 14537–14545 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. Lawrence, J. L. et al. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment. J. Neurosci. 34, 14210–14218 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  205. Schonherr, C. et al. Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site. Mol. Neurodegener. 11, 19 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. Song, D. K. et al. Behavioral and neuropathologic changes induced by central injection of carboxyl-terminal fragment of β-amyloid precursor protein in mice. J. Neurochem. 71, 875–878 (1998).

    CAS  PubMed  Article  Google Scholar 

  207. Nalbantoglu, J. et al. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387, 500–505 (1997).

    CAS  PubMed  Article  Google Scholar 

  208. Berger-Sweeney, J. et al. Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res. Mol. Brain Res. 66, 150–162 (1999).

    CAS  PubMed  Article  Google Scholar 

  209. Lauritzen, I. et al. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 132, 257–276 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. Ghosal, K. et al. Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc. Natl Acad. Sci. USA 106, 18367–18372 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  211. Giliberto, L., d'Abramo, C., Acker, C. M., Davies, P. & D'Adamio, L. Transgenic expression of the amyloid-β precursor protein-intracellular domain does not induce Alzheimer's disease-like traits in vivo. PLoS ONE 5, e11609 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank C. Bold, A. Mehr and M. Richter for help with figure preparation. The authors' work is supported by the Deutsche Forschungsgemeinschaft (FOR1332 on “Physiological functions of the APP gene family”) and the Alzheimer Research Prize of the Breuer Foundation to U.C.M.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ulrike C. Müller.

Ethics declarations

Competing interests

T.D. and M.K. declare no competing interests. U.C.M. is listed as a co-inventor on a patent application aiming to use APPsα for Alzheimer disease therapy.

Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Selected APP interactors. (PDF 711 kb)

Glossary

Synaptophysin

A presynaptic glycoprotein located in the membrane of synaptic vesicles that is regularly used as a marker for synapses.

Recycling endosomes

A form of early endosomes responsible for recycling membrane proteins, including receptors, back to the plasma membrane. They connect the endocytic pathway to the exocytic pathway.

Endoproteolytic

Cleavage of an internal peptide bond in a polypeptide or protein.

Exoproteolytic

Cleavage of peptide bonds from the end of a polypeptide chain.

Hemisynapses

Presynaptic specializations without a neuronal postsynaptic site. They contain presynaptic marker proteins, including proteins of the active zone and synaptic vesicles.

Retinotectal axons

Nerve fibres connecting the retina to nuclei in the tectum.

Necroptosis

A form of regulated, necrotic cell death that involves death receptors and the activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3.

Cortical plate

The last plate formed in the anlage of the mammalian cortex; it matures into cortical layers II–VI.

Marginal zone

Zone arising from the cortical preplate during corticogenesis. It contains Cajal–Retzius cells, which regulate radial neuronal migration, and it matures into cortical layer I.

Lamellipodia

Cellular protrusions formed during cell migration at the leading edge of motile cells or motile cell processes. They contain microfilaments that pull the cell forwards.

APP/PS1 mice

Transgenic Alzheimer disease (AD) model that exhibits plaque pathology; the mice overexpress amyloid precursor protein (APP) with a humanized amyloid-β region with the human Swedish double mutation and the AD-associated ΔE9 variant of presenilin 1.

Paired-pulse facilitation

(PPF). A form of short-term synaptic plasticity in which a second excitatory postsynaptic potential is increased when that stimulus closely follows a prior stimulation.

Aη-α

Amyloid precursor protein (APP) fragment generated by combined cleavage of η-secretase and α-secretase.

Excitotoxic

Resulting from the overactivation of glutamate receptors, and potentially toxic to certain neurons.

Minimal functional domains

The smallest domains or polypeptide stretches that exhibit the same functional properties as larger proteins.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Müller, U., Deller, T. & Korte, M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18, 281–298 (2017). https://doi.org/10.1038/nrn.2017.29

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2017.29

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing