The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.

2.50
Hdl Handle:
http://hdl.handle.net/10033/615495
Title:
The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.
Authors:
Klevanski, Maja; Herrmann, Ulrike; Weyer, Sascha W; Fol, Romain; Cartier, Nathalie; Wolfer, David P; Caldwell, John H; Korte, Martin; Müller, Ulrike C
Abstract:
The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. 2015, 35 (49):16018-33 J. Neurosci.
Journal:
The Journal of neuroscience : the official journal of the Society for Neuroscience
Issue Date:
9-Dec-2015
URI:
http://hdl.handle.net/10033/615495
DOI:
10.1523/JNEUROSCI.2009-15.2015
PubMed ID:
26658856
Type:
Article
Language:
en
ISSN:
1529-2401
Appears in Collections:
publications of the research group neuroinflammation and neurodegeneration (NIND)

Full metadata record

DC FieldValue Language
dc.contributor.authorKlevanski, Majaen
dc.contributor.authorHerrmann, Ulrikeen
dc.contributor.authorWeyer, Sascha Wen
dc.contributor.authorFol, Romainen
dc.contributor.authorCartier, Nathalieen
dc.contributor.authorWolfer, David Pen
dc.contributor.authorCaldwell, John Hen
dc.contributor.authorKorte, Martinen
dc.contributor.authorMüller, Ulrike Cen
dc.date.accessioned2016-07-05T08:44:37Z-
dc.date.available2016-07-05T08:44:37Z-
dc.date.issued2015-12-09-
dc.identifier.citationThe APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. 2015, 35 (49):16018-33 J. Neurosci.en
dc.identifier.issn1529-2401-
dc.identifier.pmid26658856-
dc.identifier.doi10.1523/JNEUROSCI.2009-15.2015-
dc.identifier.urihttp://hdl.handle.net/10033/615495-
dc.description.abstractThe amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAlzheimer Diseaseen
dc.subject.meshAmyloid beta-Peptidesen
dc.subject.meshAmyloid beta-Protein Precursoren
dc.subject.meshAnimalsen
dc.subject.meshDisease Models, Animalen
dc.subject.meshExcitatory Postsynaptic Potentialsen
dc.subject.meshExploratory Behavioren
dc.subject.meshHippocampusen
dc.subject.meshHoming Behavioren
dc.subject.meshMaze Learningen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Transgenicen
dc.subject.meshMuscle Strengthen
dc.subject.meshMutationen
dc.subject.meshNeural Conductionen
dc.subject.meshNeuronal Plasticityen
dc.subject.meshPhrenic Nerveen
dc.subject.meshProtein Structure, Tertiaryen
dc.subject.meshSynapsesen
dc.titleThe APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalThe Journal of neuroscience : the official journal of the Society for Neuroscienceen

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