Apolipoprotein-E modulates the cytotoxic effect of beta-amyloid on rat brain endothelium in an isoform-dependent specific manner.
Several studies support the hypothesis that apolipoprotein-E (ApoE) acts as a pathological chaperone protein that promotes the beta-plated sheet conformation of beta-amyloid (Abeta) peptides into amyloid fibers. In vitro evidence is also available that ApoE inhibits the neurotoxic effect of Abeta in an allele-specific manner (E2 > or = E3 > E4). We have recently shown that Abeta peptides exert a time- and concentration-dependent toxic effect on rat neuromicrovascular endothelial cells (NECs), and this study aimed to ascertain whether ApoE isoforms are able to modulate this effect. ApoE2 and ApoE4 decreased and increased, respectively, the cytotoxic effect of Abeta(1-40) and Abeta(1-42) on NECs, as evaluated by their survival and viability rates. The toxic effect of both Abeta peptides and ApoE4 was associated with the rise in the necrosis rate of NECs within a 24-h incubation period. Moreover, ApoE2 prevented and ApoE4 magnified the inhibitory effect of Abeta on the capability of NECs cultured on Matrigel to form a capillary-like network. The opposite effects of ApoE isoforms could be due to their different interactions with the C-terminal domain of Abeta. ApoE2, at variance with ApoE4, is thought to form sodium dodecyl sulphate-stable complexes with Abeta and, as a consequence, it could block the interactions of the non-fibrillar Abeta peptide with the plasma membrane, Abeta peptide aggregation and the ensuing cytotoxicity. Collectively, our findings confirm the view that ApoE plays a relevant role in the pathogenesis of Alzheimer's disease.
Folin
Marcella
M
Department of Biology, University of Padua, I-35121 Padua, Italy. folin@civ.bio.unipd.it
Baiguera
Silvia
S
Guidolin
Diego
D
Di Liddo
Rosa
R
Grandi
Claudio
C
De Carlo
Eugenio
E
Nussdorfer
Gastone G
GG
Parnigotto
Pier Paolo
PP
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)