Aluminum Maltolate Induces Primary Rat Astrocyte Apoptosis via Overactivation of the Class III PI3K/Beclin 1-dependent Autophagy Signal

Toxicol In Vitro. 2012 Mar;26(2):215-20. doi: 10.1016/j.tiv.2011.11.010. Epub 2011 Nov 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • 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

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, rat
  • LC3 protein, rat
  • Microtubule-Associated Proteins
  • Organometallic Compounds
  • Pyrones
  • aluminum maltolate
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Caspase 3