The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-b 1e42 in the rat hippocampus in vivo Rachael M. Clarke 1 , Florence O’Connell 1 , Anthony Lyons, Marina A. Lynch * Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland Received 29 May 2006; received in revised form 22 July 2006; accepted 24 July 2006 Abstract One response of the brain to stressors is to increase microglial activation with the consequent production of proinflammatory cytokines like interleukin-1b (IL-1b), 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-b (Ab) peptides increase activation of microglia, while its inhibitory effect on LTP is well documented, and associated with the Ab-induced increase in IL-1b. Here we set out to establish whether the Ab-induced inhibition of LTP 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 Ab on LTP. We report that intracerebroventricular injection of Ab increased expression of several markers of microglial activation, and in parallel, inhibited LTP in dentate gyrus. The data show that atorvastatin abrogated the Ab-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. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Long-term potentiation; Microglial activation; Interleukin-1b; Inflammation; Amyloid-b; Hippocampus; Atorvastatin 1. Introduction Although historically considered to be an immunoprivileged organ, the brain is now known to respond to inflammatory stim- uli, and inflammatory changes are identified as one character- istic of many neurodegenerative conditions. Microglia are the major resident immunocompetent cells in the brain and conse- quently play a particular role in immunomodulation (Benveniste, 1997; Rio-Hortega, 1932). Under normal conditions, microglia are maintained in a quiescent state by virtue of the absence of stimulatory factors like interferon-g which are only released in times of stress or injury (Neumann, 2001), and as a conse- quence of their interaction with other cells, including neurons (Hoek et al., 2000; Lyons et al., 2005). However microglia become activated, a state characterized by altered morphology and expression of cell surface molecules (Akiyama et al., 2000), in response to insult or injury and release reactive oxygen and nitrogen species and proinflammatory cytokines (Minagar et al., 2002; Neumann, 2001). Thus the increase in hippocampal concentration of the proinflammatory cytokine, interleukin (IL)-1b, which occurs in the brain of aged rats (Lynch et al., in press) and amyloid-b (Ab)-treated rats (Minogue et al., 2003), is associated with microglial activation as assessed by increased expression of major histocompatibil- ity complex II (MHCII). The age-related increase in MHCII expression has also been coupled with increases in expression of the glycoprotein, intercellular adhesion molecule-1 (ICAM- 1), the co-stimulatory molecule, CD86 and also CD40 (Griffin et al., in press), which are expressed on microglia (Carreno and Collins, 2002; Lee et al., 2000; Minagar et al., 2002) as well as other cell types. Up-regulated expression of chemokines such * Corresponding author. Tel.: þ353 1 896 8531; fax: þ353 1 679 3545. E-mail address: lynchma@tcd.ie (M.A. Lynch). 1 These authors contributed equally to this work. 0028-3908/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2006.07.031 Neuropharmacology 52 (2007) 136e145 www.elsevier.com/locate/neuropharm