Regulation of Neurotransmitter Release by Amyloid Precursor Protein Through Synapsin Phosphorylation
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Abnormal processing of amyloid precursor protein (APP) and aggregation of the Aβ peptide are known to play a key role in the pathogenesis of Alzheimer disease, but the function of endogenous APP under normal physiological conditions remains poorly understood. In this study, we investigated presynaptic changes in APP knockout (KO) mice. We demonstrate that both sucrose-induced neurotransmission and synaptic depletion in response to high frequency stimulation are significantly enhanced in APP KO compared to wild type littermates. In addition, the level of phosphorylated forms of synapsins, but not total synapsins, is elevated in the KO mice. Furthermore, we show that the inhibition of L-type calcium channels normalizes phosphorylated synapsins and slows down the high frequency induced synaptic depletion in APP KO mice. These results suggest a new mechanism by which APP regulates synaptic vesicle dynamics through synapsin-dependent phosphorylation.
KeywordsAlzheimer disease Amyloid precursor protein Synaptic depletion Synapsin Ca2+ channel
We thank all members of Jia lab for their technical assistance and comments on the manuscript.
This work was supported by Grants from the Canadian Institutes of Health Research (CIHR, MOP119421, ZPJ), Canadian Natural Science and Engineering Research Council (NSERC, RGPIN341498, ZPJ), Natural Science Foundation of China (NSFC 31200805, ZZ), NSFC and CIHR Joint Health Research Initiative Program (81161120543, WX and CCI117959, ZPJ), National Postdoctoral Program for Innovative Talents (1131000,047, AL) and Brain Canada (ZPJ).
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