title: Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells.
abstract: We examined the effect of the three human isoforms of apolipoprotein E (ApoE2, ApoE3, and ApoE4) on the canonical Wnt signaling pathway in undifferentiated PC12 cells. Addition of recombinant ApoE4 reduced Wingless-Int7a-stimulated gene expression at concentrations of 80 and 500 nm. Recombinant ApoE2 and ApoE3 were virtually inactive. Recombinant ApoE4 also inhibited Wnt signaling when combined with very low density lipoproteins (VLDLs) or in cells over-expressing the low density lipoprotein receptor-related protein, LRP6. In contrast, the enforced expression of LRP5 unmasked an inhibition by ApoE2 and ApoE3, which, however, were less effective than ApoE4 in inhibiting Wnt signaling. We also transfected PC12 cells with constructs encoding for the three human ApoE isoforms to examine whether endogenously expressed ApoE isoforms could modulate the Wnt pathway. Under these conditions, all three ApoE isoforms were able to inhibit Wnt signaling, although ApoE4 showed the greatest efficacy. Only the conditioned medium collected from cultures transfected with ApoE4 induced a significant inhibition of Wnt7a-stimulated gene expression, confirming that ApoE4 has an extracellular action that is not shared by the other ApoE isoforms. We conclude that ApoE4 behaves as an inhibitor of the canonical Wnt pathway in a context-independent manner.
authors.affiliation: Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caruso
authors.forename: Marta
authors.initials: M
authors.lastname: Motolese
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Georg C
authors.initials: GC
authors.lastname: Terstappen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaviraghi
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D003470:Culture Media; D016716:PC12 Cells; D010957:Plasmids; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014162:Transfection; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D003470:Culture Media; D051153:Wnt Proteins; D051176:beta Catenin