title: The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.
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.
  
  
  CONCLUSIONS
  Synaptic dysfunction and cognitive decline are early hallmark features of Alzheimer's disease. Thus, it is essential to elucidate the in vivo function(s) of APP at the synapse. At present, it is unknown whether APP family proteins function as cell surface receptors, or mainly via shedding of their secreted ectodomains, such as neurotrophic APPsα. Here, to dissect APP functional domains, we used APP mutant mice lacking the last 15 amino acids that were crossed onto an APLP2-KO background. These APPΔCT15-DM mice showed defects in neuromuscular morphology and function. Synaptic deficits in the CNS included impairments of synaptic plasticity, spatial learning, and memory. Collectively, this indicates that multiple APP domains, including the C-terminus, are required for normal nervous system function.
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Klevanski
authors.affiliation: Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Herrmann
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Sascha W
authors.initials: SW
authors.lastname: Weyer
authors.affiliation: INSERM U1169/MIRCen CEA Fontenay aux Roses, 92265, and Université Paris-Sud, University Paris-Saclay, Orsay 94100, France, Université Paris Descartes, 75006 Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fol
authors.affiliation: INSERM U1169/MIRCen CEA Fontenay aux Roses, 92265, and Université Paris-Sud, University Paris-Saclay, Orsay 94100, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: Institute of Anatomy, University of Zurich and Institute of Human Movement Sciences, ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: David P
authors.identifier: http://orcid.org/0000-0002-5957-1401
authors.initials: DP
authors.lastname: Wolfer
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado, Aurora, Colorado 80045, and.
authors.forename: John H
authors.initials: JH
authors.lastname: Caldwell
authors.affiliation: Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany, AG NIND, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany, u.mueller@urz.uni-hd.de.
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D006624:Hippocampus / Q000473:pathology*; D006702:Homing Behavior / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D010791:Phrenic Nerve / Q000503:physiopathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D013569:Synapses / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse
keywords: Alzheimer's disease; amyloid precursor protein; behavior; knockin; signaling; synaptogenesis