The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-beta(1-42) in the rat hippocampus in vivo

One response of the brain to stressors is to increase microglial activation with the consequent production of proinflammatory cytokines like interleukin-1 beta (IL-1 beta), which has been shown to exert an inhibitory effect on long-term potentiation (LTP) in the hippocampus. It has been consistently shown, particularly in vitro, that amyloid-beta (A beta) peptides increase activation of microglia, while its inhibitory effect on UP is well documented, and associated with the A beta-induced increase in IL-1 beta. Here we set out to establish whether the A beta-induced inhibition of UP in perforant path-granule cell synapses, was coupled with evidence of microglial activation and to assess whether atorvastatin, which is used primarily in the treatment of hyperlipidaemia but which possesses anti-inflammatory properties, might modulate the effect of AD on LTP. We report that intracerebroventricular injection of A beta increased expression of several markers of microglial activation, and in parallel, inhibited LTP in dentate gyrus. The data show that atorvastatin abrogated the A beta-induced microglial activation and the associated deficit in LTP On the basis of the evidence presented, we propose that the action of atorvastatin is mediated by its ability to increase production of the anti-inflammatory cytokine, interleukin-4, which we report mimics several of the actions of atorvastatin in the rat hippocampus. (c) 2006 Elsevier Ltd. All rights reserved.