Acetyl-Ile-Gly-Leu protects neurons from Abeta(1-42) induced toxicity in vitro and in V337M human tau-expressing mice.
OBJECTIVE
We previously reported that the neurotoxicity of amyloid beta protein (Abeta(1-42), 10 nM) was blocked by an Abeta-derived tripeptide, Abeta(32-34) (Ile-Gly-Leu, IGL), suggesting that IGL may be a lead compound in the design of Abeta antagonists. In the present study, three stable forms of IGL peptide with acetylation of its N-terminal and/or amidation of its C-terminal (acetyl-IGL, IGL-NH(2) and acetyl-IGL-NH(2)) were synthesized and examined for their effects on Abeta-induced neurotoxicity.


METHODS
Phosphatidylinositol 4-kinase type II (PI4KII) activity was measured using recombinant human PI4KIIalpha kinase and cell viability was assessed in primary cultured hippocampal neurons. To test effects in vivo, 1.5 microl of 100 nM Abeta and/or 100 nM acetyl-IGL was injected into the hippocampal CA1 region of right hemisphere in transgenic mice expressing V337M human tau protein. Four weeks later, behavior performance in the Morris water maze was tested and after another 2 weeks, sections of brain were prepared for immunohistochemistry.


RESULTS
Among the three modified tripeptides, acetyl-IGL attenuated the Abeta-induced inhibition of PI4KII activity as well as enhancement of glutamate neurotoxicity in primary cultured rat hippocampal neurons. Injection of Abeta into the hippocampus of mice impaired spatial memory and increased the number of degenerating neurons in bilateral hippocampal regions. Co-injection of acetyl-IGL prevented the learning impairment as well as the neuronal degeneration induced by Abeta.


CONCLUSIONS
These results suggest that a modified tripeptide, acetyl-IGL, may be effective in the treatment of Alzheimer's disease.
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
Nakamura
Tomoyuki
T
Inagaki
Chiyoko
C
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000633:toxicity*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C539350:acetyl-isoleucyl-glycyl-leucine; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019870:1-Phosphatidylinositol 4-Kinase