%0 Journal Article
%T Heme oxygenase-1 derived carbon monoxide suppresses A¦Â1¨C42 toxicity in astrocytes
%A Chris Peers
%A Jason L Scragg
%A John P Boyle
%A Mark L Dallas
%A Moza M Al-Owais
%A Nishani T Hettiarachchi
%J Archive of "Cell Death & Disease".
%D 2017
%R 10.1038/cddis.2017.276
%X Neurodegeneration in Alzheimer¡¯s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid ¦Â peptides ((A¦Â; the widely accepted major toxic factor in AD) is less well understood. Here, we show that A¦Â(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, A¦Â(1-42) raises peroxynitrite levels in astrocytes, and A¦Â(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following A¦Â(1-42) application were derived from NADPH oxidase. Induction of haem oxygenase-1 (HO-1) protected astrocytes from A¦Â(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by A¦Â(1-42). Under hypoxic conditions (0.5% O2, 48£¿h) HO-1 was induced in astrocytes and A¦Â(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that A¦Â(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520931/