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  APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone

Lassek, M., Weingarten, J., Wegner, M., Mueller, B. F., Rohmer, M., Baeumlisberger, D., et al. (2016). APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone. PLoS Comput Biol, 12(4), e1004832. doi:10.1371/journal.pcbi.1004832.

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Lassek, M., Author
Weingarten, J., Author
Wegner, M., Author
Mueller, B. F., Author
Rohmer, M., Author
Baeumlisberger, D., Author
Arrey, T. N., Author
Hick, M., Author
Ackermann, J., Author
Acker-Palmer, Amparo1, Author              
Koch, I., Author
Muller, U., Author
Karas, M., Author
Volknandt, W., Author
Affiliations:
1Neurovascular interface Group, Max Planck Institute for Brain Research, Max Planck Society, ou_2461707              

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Free keywords: Alzheimer Disease/etiology/metabolism Amyloid beta-Protein Precursor/deficiency/genetics/*metabolism Animals Computational Biology Hippocampus/*metabolism Humans Mice Mice, Inbred C57BL Mice, Knockout Presynaptic Terminals/metabolism Protein Interaction Maps Proteome/metabolism Synapses/metabolism
 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 Abeta-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.

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 Dates: 2016-04-20
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: Other: 27092780
DOI: 10.1371/journal.pcbi.1004832
ISSN: 1553-7358 (Electronic)1553-734X (Linking)
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Title: PLoS Comput Biol
Source Genre: Journal
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Pages: - Volume / Issue: 12 (4) Sequence Number: - Start / End Page: e1004832 Identifier: -