APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.
The hallmarks of Alzheimer's disease (AD) are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP) has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ) highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs) was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI) networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.
Institute for Cell Biology and Neuroscience, Biologicum, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Melanie
M
Laßek
Institute for Cell Biology and Neuroscience, Biologicum, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Jens
J
Weingarten
Institute for Molecular Bioinformatics, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Martin
M
Wegner
Institute of Pharmaceutical Chemistry, Cluster of Excellence "Macromolecular Complexes", Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Benjamin F
BF
Mueller
Institute of Pharmaceutical Chemistry, Cluster of Excellence "Macromolecular Complexes", Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Marion
M
Rohmer
SunChrom Wissenschaftliche Geräte GmbH, Friedrichsdorf, Germany.
Dominic
D
Baeumlisberger
Thermo Fisher Scientific, Bremen, Germany.
Tabiwang N
TN
Arrey
Department of Pharmacy and Molecular Biotechnology, University Heidelberg, Heidelberg Germany.
Meike
M
Hick
Institute for Molecular Bioinformatics, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Jörg
J
Ackermann
Institute for Cell Biology and Neuroscience, Biologicum, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Amparo
A
Acker-Palmer
Institute for Molecular Bioinformatics, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Ina
I
Koch
Department of Pharmacy and Molecular Biotechnology, University Heidelberg, Heidelberg Germany.
Ulrike
U
Müller
Institute of Pharmaceutical Chemistry, Cluster of Excellence "Macromolecular Complexes", Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Michael
M
Karas
Institute for Cell Biology and Neuroscience, Biologicum, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Walter
W
Volknandt
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019295:Computational Biology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017729:Presynaptic Terminals / Q000378:metabolism; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D020543:Proteome