Blockade of caspase-1 increases neurogenesis in the aged hippocampus.
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-1beta 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-1beta 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-1beta 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.
Gemma
Carmelina
C
Center of Excellence for Ageing and Brain Repair, Department of Neurosurgery, University of South Florida, and James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd., Tampa, FL 33612, USA. cgemma@health.usf.edu
Bachstetter
Adam D
AD
Cole
Michael J
MJ
Fister
Matthew
M
Hudson
Charles
C
Bickford
Paula C
PC
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D014404:Tubulin; D020170:Caspase 1; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine