title: Aluminum maltolate induces primary rat astrocyte apoptosis via overactivation of the class III PI3K/Beclin 1-dependent autophagy signal.
abstract: 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.
authors.affiliation: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Zeng
authors.forename: Hong
authors.initials: H
authors.lastname: Fu
authors.forename: Geng-Xin
authors.initials: GX
authors.lastname: Liu
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011753:Pyrones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D053148:Caspase 3; D008869:Microtubule-Associated Proteins; D009942:Organometallic Compounds; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011753:Pyrones; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C067527:aluminum maltolate; C499322:Parp1 protein, rat