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Neurodegenerative disorders
Author(s) -
Lin, KF,
Chang, RCC,
Yu, MS,
Suen, KC,
Hugon, J
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j..2003.0c7-1.x
Subject(s) - citation , computer science , psychology , information retrieval , library science
Accumulation of Ab peptides has been considered to play important roles in thepathogenesis of Alzheimer’s disease (AD). Ab neurotoxicity is mediated via awide array of intracellular signaling pathways including increases in intracellularcalcium, different mitogen activated kinases and caspases. We have recentlyshown that attenuation of intracellular calcium provides significant but partialneuroprotective effect only. While endoplasmic reticulum (ER) stress responsesare not early activated right after exposure to Ab, phosphorylation of eukaryoticinitiation factor 2a (eIF2a) are detected at early time points. The roles of PKR arethus intensively studied from our group. We are the first laboratory to show theinvolvement of PKR in Ab neurotoxicity. PKR not just involves but playssignificant roles in Ab neurotoxicity. Over-expression of negatively mutatedneuroblastoma cells as well as primary cultured neurons from PKR knockout micedemonstrate a marked reduction of neuronal death. Postmortem AD brain sectionsalso elicit high immunoreactivity for phosphorylated PKR and eIF2a. We haverecently shown the upstream pathways for PKR to be activated by Ab. Early andmild activation of caspase-3 can function as signaling molecule mediatingactivation of PKR. Taken together, while PKR is not specific for Ab neurotoxicityand for AD, it will trigger pro-apoptotic signaling cascade in neurons once it isactivated. PKR may become a new potential pharmaceutical target for developingneuroprotective agent.link_to_subscribed_fulltex