title: 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.affiliation: Department of Pharmacology, CMRI, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Young-Pyo
authors.initials: YP
authors.lastname: Nam
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Jeon
authors.forename: Hyung-Soo
authors.initials: HS
authors.lastname: Han
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007150:Immunohistochemistry; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; D008668:Metallothionein