APP Deletion Accounts for Age-Dependent Changes in the Bioenergetic Metabolism and in Hyperphosphorylated CaMKII at Stimulated Hippocampal Presynaptic Active Zones.
Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Melanie
M
Laßek
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Jens
J
Weingarten
Molecular Bioinformatics, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Martin
M
Wegner
Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Moritz
M
Neupärtl
Thermo Fisher Scientific Bremen, Germany.
Tabiwang N
TN
Array
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-UniversitätFrankfurt, Germany; Max Planck Institute for Brain ResearchFrankfurt, Germany.
Eva
E
Harde
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Benedikt
B
Beckert
Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Vahid
V
Golghalyani
Molecular Bioinformatics, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Jörg
J
Ackermann
Molecular Bioinformatics, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Ina
I
Koch
Department of Pharmacy and Molecular Biotechnology, University Heidelberg Heidelberg, Germany.
Ulrike C
UC
Müller
Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Michael
M
Karas
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-UniversitätFrankfurt, Germany; Max Planck Institute for Brain ResearchFrankfurt, Germany.
Amparo
A
Acker-Palmer
Institute for Cell Biology and Neuroscience, Biologicum and BMLS, Johann Wolfgang Goethe-Universität Frankfurt, Germany.
Walter
W
Volknandt
LTP; aging; amyloid precursor protein; hippocampus; mitochondria; presynaptic active zone