期刊
JOURNAL OF NEUROSCIENCE
卷 42, 期 49, 页码 9253-9262出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0297-22.2022
关键词
Alzheimer?s disease; APP; kainate receptors; presenilin; synapse
资金
- Centre National de la Recherche Scientifique (CNRS)
- French ANR (Agence Nationale de la Recherche) PREPLASH Project grant
- Fondation France Alzheimer
- Erasmus Mundus program European Neuroscience Campus from Seventh Framework Programme
Kainate receptors (KARs) play a role in regulating neuronal networks and have been implicated in epilepsy. This study investigates the role of KARs in Alzheimer's disease (AD) and finds that the synaptic expression and function of KARs are impaired in mouse models of AD. The study also suggests that the protein APP stabilizes KARs at synapses through a transsynaptic mechanism, and this interaction is regulated by the c-secretase proteolytic activity of presenilin.
Kainate receptors (KARs) form a family of ionotropic glutamate receptors that regulate the activity of neuronal networks by both presynaptic and postsynaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer's disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude and decay time of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells in male and female mice with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with c-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a transsynaptic mechanism, and this interaction is under the control the c-secretase proteolytic activity of presenilin.
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