Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2− production
- 16 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 23 (12), 1555-1566
- https://doi.org/10.1038/s41593-020-00735-y
Abstract
Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer’s disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2−-induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.Funding Information
- U.S. Department of Health & Human Services | NIH | Center for Information Technology (AG059236-01A1)
- Cure Alzheimer’s Fund
- U.S. Department of Health & Human Services | NIH | Center for Scientific Review (AG054156)
- National Research Foundation of Korea (NRF-2016M3C7A1904233, 2015R1A3A2066619, 2018M3C7A1056682 and 2018M3C7A1056897)
- Korea Institute of Science and Technology (2E26663, 2E28411)
- MSIP | Institute for Information and communications Technology Promotion (CRC-15-04-KIST)
- Institute for Basic Science (IBS-R001-D2)
This publication has 52 references indexed in Scilit:
- Elucidating the Interactive Roles of Glia in Alzheimer's Disease Using Established and Newly Developed Experimental ModelsFrontiers in Neurology, 2018
- Reactive astrocytes in Alzheimer's disease: A double-edged swordNeuroscience Research, 2017
- Elusive roles for reactive astrocytes in neurodegenerative diseasesFrontiers in Cellular Neuroscience, 2015
- GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild‐type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's diseaseGlia, 2015
- The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer's and Huntington's DiseasesJournal of Neuroscience, 2015
- Heterogeneity of reactive astrocytesNeuroscience Letters, 2014
- Reactive Glia in the Injured Brain Acquire Stem Cell Properties in Response to Sonic HedgehogCell Stem Cell, 2013
- Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 miceThe FASEB Journal, 2012
- Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascadeThe Lancet Neurology, 2010
- Molecular dissection of reactive astrogliosis and glial scar formationTrends in Neurosciences, 2009