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Autophagy. 2009 May;5(4):502-10. Epub 2009 May 6.

Autophagy protects neuron from Abeta-induced cytotoxicity.

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Pharmacological Institute, College of Medicine, National Taiwan University, No. 1 Sec. 1 Jen-Ai Road, Taipei, Taiwan.


Autophagy is a degradation pathway for the turnover of dysfunctional organelles or aggregated proteins in cells. Extracellular accumulation of beta-amyloid peptide has been reported to be a major cause of Alzheimer disease (AD) and large numbers of autophagic vacuoles accumulate in the brain of AD patient. However, how autophagic process is involved in Abeta-induced neurotoxicity and how Abeta peptide is transported into the neuron and metabolized is still unknown. In order to study the role of autophagic process in Abeta-induced neurotoxicity, EGFP-LC3 was overexpressed in SH-SY5Y cells (SH-SY5Y/pEGFP-LC3). It was found that treatment with Abeta(25-35), Abeta(1-42) or serum-starvation induced strong autophagy response in SH-SY5Y/pEGFP-LC3. Confocal double-staining image showed that exogenous application of Abeta(1-42) in medium caused the colocalization of Abeta(1-42) with LC3 in neuronal cells. Concomitant treatment of Abeta with a selective alpha7nAChR antagonist, alpha-bungarotoxin (alpha-BTX), enhanced Abeta-induced neurotoxicity in SH-SY5Y cells. On the other hand, nicotine (nAChR agonist) enhanced the autophagic process and also inhibited cell death following Abeta application. In addition, nicotine but not alpha-BTX increased primary hippocampal neuronal survival following Abeta treatment. Furthermore, using Atg7 siRNA to inhibit autophagosome formation in an early step or alpha7nAChR siRNA to knock down alpha7nAChR significantly enhanced Abeta-induced neurotoxicity. Confocal double-staining imaging shows that nicotine treatment in the presence of Abeta enhanced the colocalization of alpha7nAChR with autophagosomes. These results suggest that alpha7nAChR may act as a carrier to bind with eAbeta and internalize into cytoplasm and further inhibit Abeta-induced neurotoxicity via autophagic degradation pathway. Our results suggest that autophagy process plays a neuroprotective role against Abeta-induced neurotoxicity. Defect in autophagic regulation or Abeta-alpha7nAChR transport system may impair the clearance of Abeta and enhance neuronal death.

[Indexed for MEDLINE]

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