Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling.
Alzheimer's disease (AD) is characterized by cognitive decline due to excess amyloid beta peptide (Abeta), neurofibrillary tangles, and neuronal loss. Abeta promotes neuronal apoptosis in AD by activating glycogen synthase kinase-3beta (GSK-3beta), leading to degradation of beta-catenin and inactivation of Wnt signaling. beta-Catenin interacts with the T-cell factor (TCF)/Lymphoid enhancer factor (LEF)-nuclear complex to mediate Wnt signaling and cell survival. Statins are associated with decreased prevalence of AD. Lovastatin has been shown to decrease the production of Abeta and to promote neuronal survival. The mechanisms of how statins promote neuronal survival are unclear. We propose that the neuroprotective effect of lovastatin may be due to inactivation of GSK-3beta activity, resulting in induction of Wnt signaling. Here, we report that lovastatin prevented Abeta-induced apoptosis in human SK-NSH cells. This was accompanied by reduction in active GSK-3beta, and increased nuclear translocation of beta-catenin, TCF-3, and LEF-1. Lovastatin treatment induced an increase in TCF/LEF-chloramphenicol acetyl transferase (CAT) gene reporter activity. More importantly, beta-catenin and TCF were required for the neuroprotective function of lovastatin. Our results suggest that lovastatin protects neuronal cells from Abeta-induced apoptosis and causes reduction in GSK-3beta activity, resulting in activation of Wnt signaling.
Salins
Pradeep
P
Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg R3E OW3, Canada.
Shawesh
Salim
S
He
Yang
Y
Dibrov
Alexander
A
Kashour
Tarek
T
Arthur
Gilbert
G
Amara
Francis
F
D016229:Amyloid beta-Peptides / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D008148:Lovastatin / Q000494:pharmacology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D007211:Indoles; D008148:Lovastatin; D051821:Lymphoid Enhancer-Binding Factor 1; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C407909:TCF3 protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C007293:DAPI