Activin A is essential for neurogenesis following neurodegeneration.
It has long been proposed that excitotoxicity contributes to nerve cell death in neurodegenerative diseases. Activin A, a member of the transforming growth factor-beta 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-beta 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.
Abdipranoto-Cowley
Andrea
A
Neuroscience Program, The Garvan Institute of Medical Research, Sydney, Australia.
Park
Jin Sung
JS
Croucher
David
D
Daniel
James
J
Henshall
Susan
S
Galbraith
Sally
S
Mervin
Kyle
K
Vissel
Bryce
B
D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018690:Excitatory Amino Acid Agonists; D008070:Lipopolysaccharides; C422405:activin A; D028341:Activins; D007608:Kainic Acid