Atorvastatin alters expression of Caveolin‐1 and PSD‐95 in Mouse Brain

Membrane/lipid rafts (MLR) are plasmalemmal microdomains enriched in sphingolipids, cholesterol and the protein caveolin (Cav) and are essential for neuronal signaling and synaptic development/stabilization. Statins inhibit HMG‐CoA reductase, the rate‐limiting enzyme involved in cholesterol biosynthesis. There exists much controversy over the effects of statins on neuronal function. We investigated the impact of long‐term atorvastatin treatment (5 mg/kg/d for 7 months by oral gavage) on cognitive behavior and brain biochemistry in mice. Atorvastatin treatment resulted in significantly longer primary escape latencies on probe trial day 1 as assessed by the Barnes maze, indicating impairment of hippocampal‐dependent short‐term memory. No motor deficits were observed as assessed by RotaRod. Sucrose gradient fraction used to isolate MLR from hippocampal tissue showed a significant reduction in the protein expression of Cav‐1 and the post‐synaptic density marker PSD‐95 from MLR in atorvastatin‐treated mice. These data suggest that statins reduce MLR protein expression, which could explain for the phenotypic changes in cognition. Such finding may provide a biochemical mechanism for neurotoxic effects from statins found in the literature.