Role of microglia and host prion protein in neurotoxicity of a prion protein fragment

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Abstract

THE prion protein PrPc is a glycoprotein of unknown function1 normally found in neurons2 and glia3. It is involved in diseases such as bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt–Jakob disease4. PrPSc, an altered isoform of PrPc that is associated with disease, shows greater protease resistance and is part of the infectious agent, the prion5,6. Prion diseases are characterized by neuronal degeneration, gliosis and accumulation of PrPSc (ref. 7). Mice devoid of PrPc are resistant to scrapie8. A fragment of human PrP consisting of amino acids 106–126 that forms fibrils in vitro is toxic to cultured neurons9–11. Here we show that this toxic effect requires the presence of microglia which respond to PrP106–126 by increasing their oxygen radical production. The combined direct and microglia-mediated effects of PrP106–126 are toxic to normal neurons but are insufficient to destroy neurons from mice not expressing PrPc.

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