Pyruvate Prevents the Inhibition of the Long-term Potentiation Induced by Amyloid-β through Protein Phosphatase 2A Inactivation

Amyloid-beta (A beta) oligomers are derived from proteolytic cleavage of amyloid-beta protein precursor and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. Pyruvate has a protective effect against A beta-induced neuronal cell death in hippocampal slice cultures. However, whether pyruvate also has a protective effect against the inhibition of neuronal plasticity induced by A beta remains to be elucidated. This study examined the effect of pyruvate on the A beta-induced inhibition of LTP in the rat hippocampus. We found that pyruvate prevented the A beta-induced inhibition of LTP as strong as fostriecin, a specific protein phosphatase 2A (PP2A) inhibitor. Pyruvate prevented the A beta block of Ca2+/calmodulin dependent protein kinase 2 (CaMK2) autophosphorylation and the A beta-induced PP2A activation. Pyruvate, but not lactate, decreased reactive oxygen species levels in CA1 slices exposed to A beta. We propose that pyruvate could prevent the A beta-induced inhibition of LTP by the re-autophosphorylation of CaMK2 through PP2A inactivation. The reduction of reactive oxygen species production is considered to be the upstream mechanism of this observed pyruvate protection.