Blockade of caspase-1 increases neurogenesis in the aged hippocampus

Carmelina Gemma, Adam D. Bachstetter, Michael J. Cole, Matthew Fister, Charles Hudson, Paula C. Bickford

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Adult hippocampal neurogenesis dramatically decreases with increasing age, and it has been proposed that this decline contributes to age-related memory deficits. Central inflammation contributes significantly to the decrease in neurogenesis associated with ageing. Interleukin-1β is a proinflammatory cytokine initially synthesized as an inactive precursor that is cleaved by caspase-1 to generate the biologically active mature form. Whether IL-1β affects neurogenesis in the aged hippocampus is unknown. Here we analysed cells positive for 5-bromo-2-deoxyuridine (BrdU; 50 mg/kg) in animals in which cleavage of IL-1β was inhibited by the caspase-1 inhibitor Ac-YVAD-CMK (10 pmol). Aged (22 months) and young (4 months) rats received Ac-YVAD-CMK for 28 days intracerebroventricularly through a brain infusion cannula connected to an osmotic minipump. Starting on day 14, animals received a daily injection of BrdU for five consecutive days. Unbiased stereology analyses performed 10 days after the last injection of BrdU revealed that the total number of newborn cells generated over a 5-day period was higher in young rats than in aged rats. In addition, there was a 53% increase in the number of BrdU-labelled cells of the aged Ac-YVAD-CMK-treated rats compared to aged controls. Immunofluorescence studies were performed to identify the cellular phenotype of BrdU-labelled cells. The increase in BrdU-positive cells was not due to a change in the proportion of cells expressing neuronal or glial phenotypes in the subgranular zone. These findings demonstrate that the intracerebroventricular administration of Ac-YVAD-CMK reversed the decrease in hippocampal neurogenesis associated with ageing.

Original languageEnglish
Pages (from-to)2795-2803
Number of pages9
JournalEuropean Journal of Neuroscience
Volume26
Issue number10
DOIs
StatePublished - Nov 2007

Keywords

  • Ageing
  • Inflammation
  • Interleukin-1β
  • Microglia
  • Rats

ASJC Scopus subject areas

  • General Neuroscience

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