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

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 (Aß). Although endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress have been implicated in Aß toxicity, the molecular mechanism(s) of Aß-induced neurotoxicity are not fully understood. In this study, we present evidence that the glia-derived stress protein metallothionein (MT) attenuates Aß-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 Aß toxicity with concurrent reduction of reactive oxygen species levels. MT reversed Aß-induced down-regulation of Bcl-2 and survival signaling in neuroblastoma cells. Moreover, MT inhibited Aß-induced proinflammatory cytokine production from microglia. The neurotoxicity of Aß-stimulated microglia was significantly attenuated by MT-I. The results indicate that MT released from reactive astrocytes may antagonize Aß neurotoxicity by direct inhibition of Aß neurotoxicity and indirect suppression of neurotoxic microglial activation. These findings broaden the understanding of neurotoxic mechanisms of Aß and the crosstalk between Aß and MT in AD.