Improvement of memory for context by inhibition of caspase-1 in aged rats

Impaired learning and memory is a common pathologic feature associated with numerous neurologic disorders. There is strong evidence that central inflammation contributes significantly to the progression of several neurodegenerative diseases as well as to the ageing process. For example, in aged rats an increase in interleukin-1beta (IL-1beta) is implicated in the decline of synaptic plasticity in the hippocampus and impaired performance on cognitive tasks such as contextual fear conditioning. IL-1beta is a proinflammatory cytokine initially synthesized in an inactive precursor form that is cleaved by caspase-1 to generate the biologically mature form. In the present study, cleavage of IL-1beta was chronically inhibited using a specific caspase-1 inhibitor (Ac-YVAD-CMK; 10 pmol) in both aged (22 month) and young (4 month) rats. Both groups received Ac-YVAD-CMK for 28 days intracerebroventricularly through a brain infusion cannula connected to an osmotic minipump. On day 20 the animals were trained in contextual fear conditioning, and memory for context was tested on day 22. Chronic infusion of a specific caspase-1 inhibitor in aged rats ameliorated age-related increases in hippocampal IL-1beta and improved memory for context.