Activin A Is Essential for Neurogenesis Following Neurodegeneration
Open Access
- 2 April 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in The International Journal of Cell Cloning
- Vol. 27 (6), 1330-1346
- https://doi.org/10.1002/stem.80
Abstract
It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-β superfamily, is expressed by neurons following excitotoxicity. We show for the first time that this activin A expression is essential for neurogenesis to proceed following neurodegeneration. We found that intraventricular infusion of activin A increased the number of newborn neurons in the dentate gyrus, CA3, and CA1 layers of the normal adult hippocampus and also, following lipopolysaccharide administration, had a potent inhibitory effect on gliosis in vivo and on microglial proliferation in vivo and in vitro. Consistent with the role of activin A in regulating central nervous system inflammation and neurogenesis, intraventricular infusion of follistatin, an activin A antagonist, profoundly impaired neurogenesis and increased the number of microglia and reactive astrocytes following onset of kainic acid-induced neurodegeneration. These results show that inhibiting endogenous activin A is permissive for a potent underlying inflammatory response to neurodegeneration. We demonstrate that the anti-inflammatory actions of activin A account for its neurogenic effects following neurodegeneration because co-administration of nonsteroidal anti-inflammatory drugs reversed follistatin's inhibitory effects on neurogenesis in vivo. Our work indicates that activin A, perhaps working in conjunction with other transforming growth factor-β superfamily molecules, is essential for neurogenesis in the adult central nervous system following excitotoxic neurodegeneration and suggests that neurons can regulate regeneration by suppressing the inflammatory response, a finding with implications for understanding and treating acute and chronic neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.Funding Information
- NHMRC Australia Grant (188819)
- NSW State Government's BioFirst Award and Spinal Cord and Related Neurological Conditions Grant
- Baxter Charitable Foundation
- Henry H Roth Charitable Foundation
- Australian Postgraduate Award
- Alma Hazel Eddy Trust
- Ramaciotti Foundation
- Ronald Geoffrey Arnott Foundation and Perpetual Trusts
- The Brain Foundation Research Grant
- K & A Collins Cancer Grant
- Adult Stem Cell Research Grant
- Lyndsay and Heather Payne Medical Research Foundation
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