Presenilin and APP Regulate Synaptic Kainate Receptors.

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Kainate receptors (KARs) are ionotropic glutamate receptors crucial for neuronal network regulation.
• KARs are implicated in epilepsy, and their role in Alzheimer's disease (AD) is increasingly questioned due to co-occurring symptoms.
• Synaptic dysfunction is a hallmark of AD, correlating with cognitive decline.

Purpose of the Study:

• To investigate the synaptic expression and function of KARs in mouse models of Alzheimer's disease.
• To determine the impact of AD-related genetic modifications and treatments on KARs.
• To elucidate the molecular mechanisms linking amyloid precursor protein (APP) processing to KAR synaptic regulation.

Main Methods:

• Immunostaining and electrophysiology were employed at mossy fiber to CA3 pyramidal cell synapses.
• Experiments utilized APP/PS1 amyloid mouse models, genetically modified mice (presenilin or APP/APLP2 deletion), and organotypic cultures treated with γ-secretase inhibitors.
• Protein-protein interaction assays were performed between GluK2 and APP fragments.

Main Results:

• A significant decrease in GluK2 immunostaining and synaptic currents mediated by GluK2-containing KARs was observed in an AD mouse model.
• Similar impairments in KAR function were found in various genetic AD models and in organotypic cultures treated with γ-secretase inhibitors.
• The GluK2 protein was found to interact with both full-length APP and its C-terminal fragments.

Conclusions:

• Synaptic KARs, particularly those containing GluK2, are impaired in Alzheimer's disease models.
• The γ-secretase activity of presenilin, processing APP, is critical for maintaining KARs at synapses, potentially via a transsynaptic mechanism.
• KARs represent a significant, yet underestimated, factor in AD-related synaptic dysfunction and cognitive deficits, warranting further investigation as therapeutic targets.