Calpain Inhibitors in Models of Alzheimer’s Disease

Calpains are calcium-activated cysteine proteases which, when abnormally activated, can initiate degradation of proteins essential for neuronal survival. A report in Journal of Clinical Investigation describes the effect of the selective calpain inhibitor, BDA-410, in a transgenic mouse model of Alzheimer’s Disease.
Calpain inhibition by BDA-410 improved spatial-working memory and associative fear memory in APP/PS1 mice. The authors put forward a hypothesis in which amyloid peptides trigger a cascade leading to calpain activation and, ultimately, synaptic dysfunction and cognitive abnormalities. BDA-410 did not alter levels of amyloid oligomers or plaque load but restored normal phosphorylation levels of transcription factor CREB and normal distribution of synaptic protein, synapsin I. These results suggest that calpain inhibition might provide a new strategy for alleviating memory loss in Alzheimer’s Disease.

BDA-410 has previously been shown to be a potent inhibitor of cysteine proteases of the malaria parasite, Plasmodium falciparum.