Inhibition of calpain prevents NMDA‐induced cell death and β‐amyloid‐induced synaptic dysfunction in hippocampal slice cultures
Open Access
- 22 March 2010
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 159 (7), 1523-1531
- https://doi.org/10.1111/j.1476-5381.2010.00652.x
Abstract
Background and purpose: Alzheimer's disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid‐β (Aβ). While the Aβ pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Aβ‐induced synaptic deficits, as well as NMDA receptor‐mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments. Experimental approach: Application of the specific, water‐soluble calpain inhibitor A‐705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Aβ‐induced deficits in neurotransmission in CA1, as well as NMDA‐induced neuronal cell death. Key results: A‐705253 dose‐dependently prevented excitotoxicity‐induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A‐705253 also fully prevented Aβ oligomer‐induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model. Conclusions and implications: We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.This publication has 37 references indexed in Scilit:
- The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neuronsNeurochemistry International, 2008
- Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral DysfunctionThe Journal of pharmacology and experimental therapeutics, 2008
- Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neuronsNeuroscience, 2007
- Calpain-Mediated mGluR1α Truncation: A Key Step in ExcitotoxicityNeuron, 2007
- Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or agingExperimental & Molecular Medicine, 2007
- The roles of intracellular protein-degradation pathways in neurodegenerationNature, 2006
- Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicityEuropean Journal of Neuroscience, 2006
- Natural oligomers of the amyloid-β protein specifically disrupt cognitive functionNature Neuroscience, 2004
- Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivoNature, 2002
- Alzheimer's Disease and Senile Dementia: Loss of Neurons in the Basal ForebrainScience, 1982