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 journalArticle

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. 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
Volume121
Issue number5
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

Fingerprint

Metallothionein
Amyloid
Alzheimer Disease
Astrocytes
Oxidative stress
Microglia
Crosstalk
Neuroblastoma
Neuroglia
Neurons
Toxicity
Oxidative Stress
Endoplasmic Reticulum Stress
Memory Disorders
Neuroprotective Agents
Therapeutic Uses
Pathology
Heat-Shock Proteins
Neurodegenerative Diseases
Cognition

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Amyloid neurotoxicity is attenuated by metallothionein : Dual mechanisms at work. / Kim, Jong Heon; Nam, Young Pyo; Jeon, Sang-Min; Han, Hyung Soo; Suk, Kyoungho.

In: Journal of Neurochemistry, Vol. 121, No. 5, 01.06.2012, p. 751-762.

Research output: Contribution to journalArticle

Kim, Jong Heon ; Nam, Young Pyo ; Jeon, Sang-Min ; Han, Hyung Soo ; Suk, Kyoungho. / Amyloid neurotoxicity is attenuated by metallothionein : Dual mechanisms at work. In: Journal of Neurochemistry. 2012 ; Vol. 121, No. 5. pp. 751-762.
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