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CaV2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.
Alexander F Jeans1, Zahid Padamsey1, Helen Collins1
1Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Cell Reports
|March 24, 2025
Summary
Alzheimer's disease oligomers disrupt synaptic function via a novel ENaC-CaV2.3-PKC-GSK-3β pathway. Inhibiting CaV2.1 channels restores normal neurotransmitter release, offering new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Synaptic dysfunction is an early hallmark of Alzheimer's disease (AD), initiated by amyloid-beta oligomers (AβOs).
- Understanding the precise mechanisms of AβO-induced synaptic defects is crucial for developing effective AD treatments.
- Existing knowledge of AβO effects on synaptic function is incomplete.
Purpose of the Study:
- To elucidate the molecular signaling pathway by which AβOs induce synaptic dysfunction in Alzheimer's disease.
- To identify novel therapeutic targets for correcting AβO-mediated synaptic defects.
Main Methods:
- Investigated the role of the epithelial sodium channel (ENaC) - CaV2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) pathway in AβO-induced synaptic dysfunction.
- Utilized human APP transgenic mouse models and human AD brain tissue.
- Examined the effects of pharmacological CaV2.1 inhibition and genetic CaV2.1 haploinsufficiency on neurotransmitter release.
Main Results:
- Uncovered a novel signaling pathway activated by AβOs involving ENaC, CaV2.3, PKC, and GSK-3β.
- Demonstrated that this pathway enhances presynaptic CaV2.1 channel activity, leading to excessive synaptic vesicle exocytosis.
- Confirmed the pathway's activity in vivo in transgenic mice and in human AD brains.
- Showed that CaV2.1 inhibition or haploinsufficiency restores normal neurotransmitter release.
Conclusions:
- Identified a previously unrecognized mechanism driving synaptic dysfunction in Alzheimer's disease.
- The ENaC-CaV2.3-PKC-GSK-3β pathway represents a significant contributor to AD pathogenesis.
- CaV2.1 channels are a promising therapeutic target for mitigating synaptic dysfunction in AD.
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