Amyloid neurotoxicity is attenuated by metallothionein: dual mechanisms at work.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognition. One of the hallmarks of AD is the accumulation of beta-amyloid (Aβ). Although endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress have been implicated in Aβ toxicity, the molecular mechanism(s) of Aβ-induced neurotoxicity are not fully understood. In this study, we present evidence that the glia-derived stress protein metallothionein (MT) attenuates Aβ-induced neurotoxicity by unique mechanisms. MT expression was increased in brain astrocytes of a NSE-APPsw transgenic mouse model of AD. Astrocyte-derived MT protected N2a neuroblastoma cells and primary cortical neurons against Aβ toxicity with concurrent reduction of reactive oxygen species levels. MT reversed Aβ-induced down-regulation of Bcl-2 and survival signaling in neuroblastoma cells. Moreover, MT inhibited Aβ-induced proinflammatory cytokine production from microglia. The neurotoxicity of Aβ-stimulated microglia was significantly attenuated by MT-I. The results indicate that MT released from reactive astrocytes may antagonize Aβ neurotoxicity by direct inhibition of Aβ neurotoxicity and indirect suppression of neurotoxic microglial activation. These findings broaden the understanding of neurotoxic mechanisms of Aβ and the crosstalk between Aβ and MT in AD.

• Authors: Jong-Heon Kim, Young-Pyo Nam, Sang-Min Jeon, Hyung-Soo Han, Kyoungho Suk
• Journal: Journal of neurochemistry (J Neurochem) Vol. 121 Issue 5 Pg. 751-62 (Jun 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22404335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Chemical References

• Amyloid beta-Peptides
• Metallothionein

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Astrocytes (metabolism)
• DNA Fragmentation
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Immunoblotting
• Immunohistochemistry
• Metallothionein (metabolism)
• Mice
• Mice, Transgenic
• Microglia (metabolism)
• Oxidative Stress (physiology)
• Reverse Transcriptase Polymerase Chain Reaction