Protective effects of Abeta-derived tripeptide, Abeta(32-34), on Abeta(1-42)-induced phosphatidylinositol 4-kinase inhibition and neurotoxicity.
We previously reported that the neurotoxicity of pathophysiological concentrations of amyloid beta proteins (Abetas, 0.1-10nM) as assessed by the inhibition of type II phosphatidylinositol 4-kinase (PI4KII) activity and the enhancement of glutamate toxicity was blocked by a short fragment of Abeta, Abeta(31-35). Such protective effects of shorter fragments derived from Abeta(31-35) were examined in this study to reach the shortest effective peptide, using recombinant human PI4KII and primary cultured rat hippocampal neurons. Among the peptides tested (Abeta(31-34), Abeta(31-33), Abeta(31-32), Abeta(32-35), Abeta(33-35), Abeta(34-35), Abeta(32-34), Abeta(33-34) and Abeta(32-33)), Abeta(31-34), Abeta(32-35) and Abeta(32-34) blocked both the Abeta(1-42)-induced inhibition of PI4KII activity and enhancement of glutamate toxicity on cell viability. The shortest peptide among them, Abeta(32-34), showed a dose-dependent protective effect with 50% effective concentration near 1nM, while Abeta(34-32), with a reverse amino acid sequence for Abeta(32-34), showed no protective effects. Thus, a tripeptide, Abeta(32-34) i.e. Ile-Gly-Leu, may be available as a lead compound for designing effective Abeta antagonists.
Xiong
Zheng-Mei
ZM
Department of Pharmacology, Kansai Medical University, Fumizono-cho 10-15, Moriguchi, Osaka 570-8506, Japan.
Kitagawa
Kaori
K
Nishiuchi
Yuji
Y
Kimura
Terutoshi
T
Inagaki
Chiyoko
C
D019870:1-Phosphatidylinositol 4-Kinase / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000187:drug effects
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019870:1-Phosphatidylinositol 4-Kinase