Aged dominant negative p38 alpha, MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

作者：Cortez IbDanelo^*; Bulavin Dmitry V; Wu Ping; McGrath Erica L; Cunningham Kathryn A; Wakamiya Maki; Papaconstantinou John; Dineley Kelly T

来源：Behavioural Brain Research, 2017, 322: 212-222.

DOI：10.1016/j.bbr.2016.10.023

• Aging
• Behavior
• Context discrimination
• Adult neurogenesis
• Fear conditioning
• Hippocampus

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.

• 出版日期2017-3-30