Amyloid neurotoxicity is attenuated by metallothionein: Dual mechanisms at work

Jong Heon Kim, Young Pyo Nam, Sang Min Jeon, Hyung Soo Han, Kyoungho Suk

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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. Metallothionein-I (MT-I) modulates Aβ-induced neurotoxicity. This study demonstrates that astrocyte-derived MT-I under neurodegenerative conditions such as Alzheimer's disease (AD) exerts neuroprotective effects via neuron-glia crosstalk. MT-I seems to be neuroprotective by modulating multiple events associated with Aβ pathology, such as inflammation, oxidative stress, and apoptosis. These findings may contribute to understanding of neurotoxic mechanisms of Aβ and suggest the therapeutic use of MT-I against AD.

Original languageEnglish (US)
Pages (from-to)751-762
Number of pages12
JournalJournal of Neurochemistry
Issue number5
StatePublished - Jun 2012
Externally publishedYes


  • Alzheimer's disease
  • beta-amyloid
  • glia
  • metallothionein
  • neurodegenerative disease
  • neuroinflammation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Amyloid neurotoxicity is attenuated by metallothionein: Dual mechanisms at work'. Together they form a unique fingerprint.

Cite this