APP is a context-sensitive regulator of the hippocampal presynaptic active zone

• Verfasst von: Laßek, Melanie [VerfasserIn]
• Verfasst von: Weingarten, Jens [VerfasserIn]
• Verfasst von: Wegner, Martin [VerfasserIn]
• Verfasst von: Mueller, Benjamin F. [VerfasserIn]
• Verfasst von: Rohmer, Marion [VerfasserIn]
• Verfasst von: Baeumlisberger, Dominic [VerfasserIn]
• Verfasst von: Arrey, Tabiwang N. [VerfasserIn]
• Verfasst von: Hick, Meike [VerfasserIn]
• Verfasst von: Ackermann, Jörg [VerfasserIn]
• Verfasst von: Acker-Palmer, Amparo [VerfasserIn]
• Verfasst von: Koch, Ina [VerfasserIn]
• Verfasst von: Müller, Ulrike C. [VerfasserIn]
• Verfasst von: Karas, Michael [VerfasserIn]
• Verfasst von: Volknandt, Walter [VerfasserIn]
• Titel: APP is a context-sensitive regulator of the hippocampal presynaptic active zone
• Verf.angabe: Melanie Laßek, Jens Weingarten, Martin Wegner, Benjamin F. Mueller, Marion Rohmer, Dominic Baeumlisberger, Tabiwang N. Arrey, Meike Hick, Jörg Ackermann, Amparo Acker-Palmer, Ina Koch, Ulrike Müller, Michael Karas, Walter Volknandt
• E-Jahr: 2016
• Jahr: April 19, 2016
• Umfang: 22 S.
• Fussnoten: Gesehen am 15.06.2020
• Titel Quelle: Enthalten in: Public Library of SciencePLoS Computational Biology
• Ort Quelle: San Francisco, Calif. : Public Library of Science, 2005
• Jahr Quelle: 2016
• Band/Heft Quelle: 12(2016,4) Artikel-Nummer e1004832, 22 Seiten
• ISSN Quelle: 1553-7358
• DOI: doi:10.1371/journal.pcbi.1004832
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cytoskeleton
• Sach-SW: Membrane proteins
• Sach-SW: Network analysis
• Sach-SW: Protein interaction networks
• Sach-SW: Protein structure networks
• Sach-SW: Proteomes
• Sach-SW: Proteomic databases
• Sach-SW: Synaptic vesicles
• K10plus-PPN: 1700575791

Abstract

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.