Statin effects on cholesterol micro-domains in brain plasma membranes.
Recent epidemiological studies revealed inhibitors of the hydroxymethylglutaryl-coenzyme A reductase, so-called statins, to be effective in lowering the prevalence of Alzheimer's disease (AD). In vitro, statins strongly reduced the cellular amyloid beta-protein load by modulating the processing of the amyloid beta precursor protein. Both observations are probably linked to cellular cholesterol homeostasis in brain. So far, little is known about brain effects of statins. Recently, we could demonstrate that treatment of mice with the lipophilic compound lovastatin resulted in a discrete reduction of brain membrane cholesterol levels. To follow up these findings, we subsequently carried out a further in vivo study including lovastatin and simvastatin as lipophilic agents, as well as pravastatin as a hydrophilic compound, focussing on their efficiency to affect subcellular membrane cholesterol pools in synaptosomal plasma membranes of mice. In contrast to the hydrophilic pravastatin, the lipophilic lovastatin and simvastatin strongly reduced the levels of free cholesterol in SPM. Interestingly, lovastatin and pravastatin but not simvastatin significantly reduced cholesterol levels in the exofacial membrane leaflet. These changes were accompanied by modified membrane bulk fluidity. All three statins reduced the expression of the raft marker protein flotillin. Alterations in transbilayer cholesterol distribution have been suggested as the underlying mechanism that forces amyloidogenic processing of APP in AD. Thus, our data give some first insight in the mode of action of statins to reduce the prevalence of AD in clinical trials.
Kirsch
Christopher
C
Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Marie-Curie-Str. 9, Germany.
Eckert
Gunter P
GP
Mueller
Walter E
WE
D000818:Animals; D016880:Anisotropy; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology; D004161:Diphenylhexatriene / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D011721:Pyrenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000737:chemistry; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D011721:Pyrenes; D047392:beta-Cyclodextrins; C106354:flotillins; C108732:methyl-beta-cyclodextrin; D004161:Diphenylhexatriene; D014302:Trinitrobenzenesulfonic Acid; D002784:Cholesterol; C030984:pyrene; D008148:Lovastatin; D019821:Simvastatin