The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons

We have previously shown that beta-amyloid (A beta) oligomers induced dynamin 1 and tau cleavage in cultured hippocampal neurons. As a result of this cleavage, dynamin I levels decreased and a toxic tau fragment was generated. A beta-induced cleavage of these proteins was calpain-mediated and impacted both synaptic vesicle recycling and the integrity of neuronal processes [Kelly, B.L., Vassar, R., Ferreira, A., 2005. Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J. Biol. Chem. 280, 31746-31753; Park, S.Y., Ferreira, A., 2005. The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J. Neurosci. 25, 5365-5375; Kelly, B.L., Ferreira, A., 2006. Betaamyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J. Biol. Chem. 281, 28079-28089, Kelly, B.L., Ferreira, A., 2007. Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons. Neuroscience 147, 60-70]. Building on previous reports, these results identified calpain as a potential target for therapeutic intervention in Alzheimer's disease. In the present study, we tested the ability of A-705253, a novel water-soluble calpain inhibitor with oral availability and enhanced metabolic stability, to prevent A beta-induced dynamin I and tau cleavage in cultured hippocampal neurons. Quantitative Western blot analysis indicated that the incubation of these cells with A-705253 prior to the addition of oligomeric A beta reduced both dynamin 1 and tau cleavage in a dose-dependent manner. In addition, our results showed that this calpain inhibitor significantly ameliorated the cleavage of these proteins when added simultaneously with oligomeric A beta. Furthermore, our data indicated that the use of this calpain inhibitor could have some beneficial effects even when added after the cleavage of these proteins have been triggered by A beta. Collectively, these results suggest that, indeed, specific calpain inhibitors could play an important role in the treatment of Alzheimer's disease. (C) 2008 Elsevier Ltd All rights reserved.