Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis.
Gas6, a product of the growth-arrest-specific gene 6, protects neurons from serum deprivation-induced apoptosis. Neuronal apoptosis is also caused by amyloid beta protein (Abeta), whose accumulation in the brain is a characteristic feature of Alzheimer's disease. Abeta induces Ca(2+) influx via L-type voltage-dependent calcium channels (L-VSCCs), leading to its neurotoxicity. In the present study, we investigated effects of Gas6 on Abeta-induced cell death in primary cultures of rat cortical neurons. Abeta caused neuronal cell death in a concentration- and time-dependent manner. Gas6 significantly prevented neurons from Abeta-induced cell death. Gas6 ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Prior to cell death, Abeta increased influx of Ca(2+) into neurons through L-VSCCs. Gas6 significantly inhibited the Abeta-induced Ca(2+) influx. The inhibitor of L-VSCCs also suppressed Abeta-induced neuronal cell death. The present cortical cultures contained few non-neuronal cells, indicating that Gas6 affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that Gas6 rescues cortical neurons from Abeta-induced apoptosis. Furthermore, the present study indicates that inhibition of L-VSCC contributes to the neuroprotective effect of Gas6.
Yagami
T
T
Discovery Research Laboratories, Shionogi and Co., Ltd., 12-4 Sagisu 5-Chome, Fukushima-ku, 553-0002, Osaka, Japan. tatsurou.yagami@shionogi.co.jp
Ueda
K
K
Asakura
K
K
Sakaeda
T
T
Nakazato
H
H
Kuroda
T
T
Hata
S
S
Sakaguchi
G
G
Itoh
N
N
Nakano
T
T
Kambayashi
Y
Y
Tsuzuki
H
H
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011506:Proteins / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099255:Growth Arrest-Specific Protein 6
D016229:Amyloid beta-Peptides; D002118:Calcium; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D000099255:Growth Arrest-Specific Protein 6