Aged dominant negative p38α, MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38 alpha) signaling pathway, we used the dominant negative mouse model for attenuated p38a activity (DN-p38 alpha(AF/+)) in which Thr180 and Tyr182 are mutated (T -> A/Y -> F) to prevent phosphorylation activation (DN-p38 alpha(AF/+),) and kinase activity. As a result, aged DN-p38 alpha(AF/+) mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38 alpha(AF/+) and wildtype littermates in a series of behavioral paradigms to test if p38 alpha mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38 alpha(AF/+) and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38 alpha(AF/+) exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38 alpha(AF/+), we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38 alpha(AF/+) mice compared to wild type littermates. Our findings support the notion that p38 alpha. inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. (C) 2016 Elsevier B.V. All rights reserved.