TY - JOUR
T1 - Blockade of caspase-1 increases neurogenesis in the aged hippocampus
AU - Gemma, Carmelina
AU - Bachstetter, Adam D.
AU - Cole, Michael J.
AU - Fister, Matthew
AU - Hudson, Charles
AU - Bickford, Paula C.
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
KW - Ageing
KW - Inflammation
KW - Interleukin-1β
KW - Microglia
KW - Rats
UR - http://www.scopus.com/inward/record.url?scp=36148964409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36148964409&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2007.05875.x
DO - 10.1111/j.1460-9568.2007.05875.x
M3 - Article
C2 - 18001276
AN - SCOPUS:36148964409
SN - 0953-816X
VL - 26
SP - 2795
EP - 2803
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 10
ER -