A putative tetrapeptide antagonist prevents beta-amyloid-induced long-term elevation of [Ca2+]i in rat astrocytes.
Comparative fluorimetric studies on the long-term (8-hour) action of beta[1-42]amyloid and its shorter fragments beta[1-40], beta[25-35] and beta[31-35] on the steady-state intracellular Ca2+ concentration in primary cultures of rat astroglial cells using the Ca2+-sensitive fluorescent probe Fura-2 AM revealed higher 340/380 fluorescence excitation ratios in the treated cells as compared to the untreated controls. All the peptides were found to induce similar cellular effects, suggesting the [31-35] region as the putative active centre of the molecule. No significant alteration was detectable in Fura-2 fluorescence using the Ca2+-insensitive excitation wavelength of 367 nm, indicating that the observed changes reflect a real alteration in the Ca2+ concentration of the cells. Moreover, no considerable difference was observed in the total protein content of treated and untreated cells. Co-treatment of the cells with Pr-Ile-Ile-Gly-Leu-NH2 (Pr-IIGL) peptide, an analogue of the [31-34] region of beta[1-42]-amyloid, was found to effectively antagonize the beta[1-42]-amyloid-induced elevation of the fluorescence excitation ratio, leaving the 367-nm fluorescence unaffected. To the best of the authors' knowledge, this is the first report on an analogue of beta-amyloid peptide capable of blocking one of its physiological effects, thereby raising the possibility that this sequence could prove to be a lead compound for designing effective beta-amyloid antagonists.
Laskay
G
G
Institute of Medical Chemistry, Albert Szent-Györgyi Medical University, Szeged, Hungary. laskayg@mdche.szote.u-szeged.hu
Zarándi
M
M
Varga
J
J
Jost
K
K
Fónagy
A
A
Torday
C
C
Latzkovits
L
L
Penke
B
B
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005456:Fluorescent Dyes; D016257:Fura-2 / Q000031:analogs & derivatives; D007700:Kinetics; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D013050:Spectrometry, Fluorescence
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C106796:propionyl-isoleucyl-isoleucyl-glycyl-leucinamide; C049925:fura-2-am; D002118:Calcium; D016257:Fura-2