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.
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.
Hughes
Mary
M
Pharmaceutical Sciences Division, King's College London, London, UK.
Snetkov
Vladimir
V
Rose
Ruth-Sarah
RS
Trousil
Sebastian
S
Mermoud
Jacqueline E
JE
Dingwall
Colin
C
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
D016564:Amyloid beta-Protein Precursor; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid