title: Neurite-like structures induced by mevalonate pathway blockade are due to the stability of cell adhesion foci and are enhanced by the presence of APP.
abstract: Epidemiological studies have shown an association between statin use and a decreased risk of dementia. However, the mechanism by which this beneficial effect is brought about is unclear. In the context of Alzheimer's disease, at least three possibilities have been studied; reduction in amyloid beta peptide (Abeta) production, the promotion of alpha-secretase cleavage and positive effects on neurite outgrowth. By investigating the effects of mevalonate pathway blockade on neurite outgrowth using real-time imaging, we found that rather than promote the production of neurite extensions, inhibition rapidly induced cell rounding. Crucially, neurite-like structures were generated through the persistence of cell-cell and cell-substrate adhesions and not through a mechanism of positive outgrowth. This effect can be strikingly enhanced by the over-expression of human amyloid precursor protein and is isoprenoid rather than cholesterol dependent.
authors.affiliation: Pharmaceutical Sciences Division, King's College London, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Hughes
authors.forename: Vladimir
authors.initials: V
authors.lastname: Snetkov
authors.forename: Ruth-Sarah
authors.initials: RS
authors.lastname: Rose
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trousil
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Mermoud
authors.forename: Colin
authors.initials: C
authors.lastname: Dingwall
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018715:Microscopy, Video / Q000379:methods; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid