Aluminum maltolate induces primary rat astrocyte apoptosis via overactivation of the class III PI3K/Beclin 1-dependent autophagy signal

• Published in: Toxicology in vitro 2012-03, Vol.26 (2), p.215-220
• Main Authors: Zeng, Ke-Wu, Fu, Hong, Liu, Geng-Xin, Wang, Xue-Mei
• Format: Article
• Language: English
• Subjects: Aluminum; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Astrocyte; Astrocytes - drug effects; Astrocytes - metabolism; Autophagy; Autophagy - drug effects; Beclin-1; Caspase 3 - metabolism; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Microtubule-Associated Proteins - metabolism; Organometallic Compounds - toxicity; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Pyrones - toxicity; Rats; Rats, Sprague-Dawley
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2011.11.010

► Aluminum significantly increased astrocyte apoptosis and autophagy levels. ► Autophagy precedes apoptosis in low dose aluminum-insulted astrocytes. ► High dose aluminum-induced serious autophagy could result in cell apoptosis. ► Aluminum-induced apoptosis is regulated by Beclin1-dependent autophagy pathway. Aluminum-induced neuronal cell apoptosis has been implicated in various neurodegenerative disorders. However, whether autophagy, a vital lysosomal degradation pathway, is involved in this pathogenesis still remains unknown. Our present findings demonstrated that aluminum significantly increased rat astrocyte apoptosis and autophagy levels in a dose-dependent manner. Examination of the associated mechanisms revealed that aluminum at low levels (400μM) did not increase apoptosis protein expressions (cleaved caspase-3 and cleaved PARP), but markedly up-regulated autophagy-related protein Beclin 1 expression. This indicates that the autophagy process occurs earlier than neuronal apoptosis. Moreover, aluminum at high levels (1600μM) significantly induced autophagy-related protein (Beclin 1 and LC3II) and apoptosis-related protein expressions, showing that both autophagy and apoptosis processes are activated under high levels of aluminum exposure. We used 3-methyladenine, an inhibitor of class III phosphatidylinositol-3 kinase, to treat astrocytes and found that the apoptosis rate in the 3-MA/aluminum co-treated group was markedly down-regulated compared with aluminum alone-treated astrocytes. The apoptosis protein and autophagy-related protein expressions were also decreased. These observations showed that the mild autophagy process may precede apoptosis in low dose aluminum-insulted astrocytes, and high dose aluminum-induced serious autophagy may result in cell apoptosis via the Beclin 1-dependent autophagy signal pathway.