title: The Amyloid Precursor Protein-A Novel Player within the Molecular Array of Presynaptic Nanomachines.
abstract: More than 20 years ago the amyloid precursor protein (APP) was identified as the precursor protein of the Aβ peptide, the main component of senile plaques in brains affected by Alzheimer's disease (AD). The pathophysiology of AD, characterized by a massive loss of synapses, cognitive decline, and behavioral changes was in principle attributed to the accumulation of Aβ. Within the last decades, much effort has gone into understanding the molecular basis of the progression of AD. However, little is known about the actual physiological function of APPs. Allocating APP to the proteome of the structurally and functionally dynamic presynaptic active zone (PAZ) highlights APP as a hitherto unknown player within the setting of the presynapse. The molecular array of presynaptic nanomachines comprising the life cycle of synaptic vesicles, exo- and endocytosis, cytoskeletal rearrangements, and mitochondrial activity provides a balance between structural and functional maintenance and diversity. The generation of genetically designed mouse models further deciphered APP as an essential player in synapse formation and plasticity. Deletion of APP causes an age-dependent phenotype: while younger mice revealed almost no physiological impairments, this condition was changed in the elderly mice. Interestingly, the proteomic composition of neurotransmitter release sites already revealed substantial changes at young age. These changes point to a network that incorporates APP into a cluster of nanomachines. Currently, the underlying mechanism of how APP acts within these machines is still elusive. Within the scope of this review, we shall construct a network of APP interaction partners within the PAZ. Furthermore, we intend to outline how deletion of APP affects this network during space and time leading to impairments in learning and memory. These alterations may provide a molecular link to the pathogenesis of AD and the physiological function of APP in the central nervous system.
authors.affiliation: Department of Molecular and Cellular Neurobiology, Goethe University Frankfurt Frankfurt am Main, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Laßek
authors.affiliation: Department of Molecular and Cellular Neurobiology, Goethe University Frankfurt Frankfurt am Main, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Weingarten
authors.affiliation: Department of Molecular Bioinformatics, Goethe University Frankfurt Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wegner
authors.affiliation: Department of Molecular and Cellular Neurobiology, Goethe University Frankfurt Frankfurt am Main, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Volknandt
keywords: Alzheimer’s disease; amyloid precursor protein; calcium homeostasis; mitochondria; presynaptic active zone
references.citation: Neuroscience. 1999;90(4):1207-16
references.pmid: 10338291
references.citation: Neurochem Int. 2000 Apr;36(4-5):471-82
references.pmid: 10733015
references.citation: Neurosci Lett. 2000 Jul 7;288(1):9-12
references.pmid: 10869803
references.citation: J Neurosci. 2000 Nov 1;20(21):7951-63
references.pmid: 11050115
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12233-8
references.pmid: 11593041
references.citation: J Neurosci. 2001 Dec 15;21(24):9744-56
references.pmid: 11739583
references.citation: Neuron. 2003 Mar 27;37(6):925-37
references.pmid: 12670422
references.citation: Biochem Pharmacol. 2003 Oct 15;66(8):1627-34
references.pmid: 14555243
references.citation: Bioessays. 2004 Apr;26(4):445-53
references.pmid: 15057942
references.citation: Acta Physiol Scand. 2004 Dec;182(4):321-31
references.pmid: 15569093
references.citation: J Neurosci. 2005 Feb 2;25(5):1219-25
references.pmid: 15689559
references.citation: J Neurosci. 2006 Jul 5;26(27):7212-21
references.pmid: 16822978
references.citation: Neuron. 2006 Dec 7;52(5):831-43
references.pmid: 17145504
references.citation: Aging Cell. 2007 Jun;6(3):337-50
references.pmid: 17328689
references.citation: Trends Neurosci. 2007 Jul;30(7):343-9
references.pmid: 17532059
references.citation: J Neurosci. 2007 Jul 18;27(29):7817-26
references.pmid: 17634375
references.citation: J Neurophysiol. 2007 Nov;98(5):2604-11
references.pmid: 17804578
references.citation: Trends Mol Med. 2008 Mar;14(3):103-8
references.pmid: 18262842
references.citation: Trends Neurosci. 2008 Sep;31(9):454-63
references.pmid: 18675468
references.citation: Circ Res. 2008 Oct 10;103(8):873-80
references.pmid: 18776040
references.citation: Biochem J. 2009 Jan 1;417(1):1-13
references.pmid: 19061483
references.citation: J Alzheimers Dis. 2009;16(1):1-14
references.pmid: 19158416
references.citation: J Alzheimers Dis. 2009;16(2):225-33
references.pmid: 19221414
references.citation: J Cell Biol. 2009 Mar 9;184(5):751-64
references.pmid: 19255244
references.citation: J Neurosci. 2009 Jul 15;29(28):9090-103
references.pmid: 19605646
references.citation: J Neurosci. 2009 Sep 2;29(35):10788-801
references.pmid: 19726636
references.citation: Trends Endocrinol Metab. 2009 Sep;20(7):332-40
references.pmid: 19733481
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057-62
references.pmid: 19897719
references.citation: J Neurosci. 2009 Dec 16;29(50):15660-8
references.pmid: 20016080
references.citation: Mol Neurobiol. 2010 Jun;41(2-3):159-71
references.pmid: 20461558
references.citation: Science. 2010 Sep 24;329(5999):1663-7
references.pmid: 20798282
references.citation: Front Neurosci. 2010 Sep 07;4:null
references.pmid: 20877425
references.citation: EMBO J. 2011 Jun 1;30(11):2266-80
references.pmid: 21522131
references.citation: Exp Brain Res. 2012 Apr;217(3-4):435-40
references.pmid: 22006270
references.citation: Cold Spring Harb Perspect Biol. 2011 Dec 01;3(12):null
references.pmid: 22026965
references.citation: Antioxid Redox Signal. 2012 Jun 15;16(12):1421-33
references.pmid: 22229260
references.citation: Mol Neurobiol. 2012 Aug;46(1):136-50
references.pmid: 22552779
references.citation: J Alzheimers Dis. 2012;31(3):459-74
references.pmid: 22571985
references.citation: Neuron. 2012 Jul 12;75(1):11-25
references.pmid: 22794257
references.citation: Mol Neurobiol. 2012 Aug;46(1):186-93
references.pmid: 22833458
references.citation: J Neurochem. 2013 Oct;127(1):48-56
references.pmid: 23815291
references.citation: Nat Med. 2013 Oct;19(10):1227-31
references.pmid: 24100992
references.citation: Neuron. 2013 Oct 30;80(3):675-90
references.pmid: 24183019
references.citation: Mol Cell Neurosci. 2014 Mar;59:106-18
references.pmid: 24534009
references.citation: Cell Tissue Res. 2015 Jan;359(1):255-65
references.pmid: 25038742
references.citation: Curr Alzheimer Res. 2014;11(10):971-80
references.pmid: 25387333
references.citation: Acta Neuropathol. 2015 Jan;129(1):21-37
references.pmid: 25432317
references.citation: Ann N Y Acad Sci. 1989;568:95-105
references.pmid: 2560904
references.citation: J Neural Transm (Vienna). 2015 Apr;122(4):541-50
references.pmid: 25742870
references.citation: Elife. 2015 Nov 09;4:e09743
references.pmid: 26551565
references.citation: Proteomes. 2015 May 13;3(2):74-88
references.pmid: 28248263
references.citation: Proteomes. 2014 Apr 24;2(2):243-257
references.pmid: 28250380
references.citation: Nature. 1987 Feb 19-25;325(6106):733-6
references.pmid: 2881207
references.citation: Neurobiol Aging. 1987 Jul-Aug;8(4):345-6
references.pmid: 3627349
references.citation: Neurobiol Aging. 1987 Jul-Aug;8(4):346-7
references.pmid: 3627350
references.citation: Biochem Biophys Res Commun. 1984 Aug 16;122(3):1131-5
references.pmid: 6236805
references.citation: Science. 1996 May 17;272(5264):1017-20
references.pmid: 8638124
references.citation: Acta Neuropathol. 1996 Sep;92(3):312-8
references.pmid: 8870835