Neuroprotective Effects of Statins in an In Vitro Model of Alzheimer's Disease
Statins, used as cholesterol-lowering drugs, were reported to reduce the progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying these findings remain to be clarified and it is not well understood whether this beneficial effect is due to simply lowering cholesterol...
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Published in | Journal of Alzheimer's disease Vol. 17; no. 3; pp. 503 - 517 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
London, England
SAGE Publications
2009
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Subjects | |
Online Access | Get full text |
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Summary: | Statins, used as cholesterol-lowering drugs, were reported to reduce the progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying these findings remain to be clarified and it is not well understood whether this beneficial effect is due to simply lowering cholesterol levels. This study was aimed to investigate the neuroprotective effect of simvastatin and lovastatin, lipophilic statins that can transverse the blood brain barrier, against the toxicity triggered by the AD-associated amyloid-β (Aβ) peptides and to analyze if such protection is cholesterol-independent. Using primary cultures of cortical neurons treated with Aβ1-40 peptide, we have demonstrated that pre-incubation with statins prevents the rise in cytosolic Ca2+ concentration and the accumulation of reactive oxygen species induced by Aβ through mechanisms independent of cholesterol reduction. The neuroprotective actions of statins were rather attributable to their ability to reduce isoprenyl intermediates levels in the cholesterol biosynthetic pathway since their effect was reversed by geranyl pyrophosphate while cholesterol addition was ineffective. Consequently, statins were shown to rescue cortical neurons from Aβ1-40-induced caspase-3-dependent apoptosis. Moreover, our results revealed that simvastatin, at neuroprotective concentrations against Aβ-induced toxicity, is not able to activate Akt or ERK2, two signaling kinases with neuroprotective roles against apoptosis. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1387-2877 1875-8908 |
DOI: | 10.3233/JAD-2009-1067 |