The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Weyer, Sascha W
Wolfer, David P
Caldwell, John H
Müller, Ulrike C
MetadataShow full item record
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.
CitationThe APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. 2015, 35 (49):16018-33 J. Neurosci.
AffiliationHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity.
- Authors: Hick M, Herrmann U, Weyer SW, Mallm JP, Tschäpe JA, Borgers M, Mercken M, Roth FC, Draguhn A, Slomianka L, Wolfer DP, Korte M, Müller UC
- Issue date: 2015 Jan
- APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.
- Authors: 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, Jäschke A, Korte M, Wolfer DP, Caldwell JH, Müller UC
- Issue date: 2011 Jun 1
- Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice.
- Authors: Wu M, Shi H, He Y, Yuan L, Qu X, Zhang J, Wang Z, Cai H, Qi J
- Issue date: 2017
- APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission.
- Authors: Schilling S, Mehr A, Ludewig S, Stephan J, Zimmermann M, August A, Strecker P, Korte M, Koo EH, Müller UC, Kins S, Eggert S
- Issue date: 2017 May 24
- Treadmill exercise enhances synaptic plasticity, but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice.
- Authors: Zhao G, Liu HL, Zhang H, Tong XJ
- Issue date: 2015 Jul 9