| First Author | Cortez I | Year | 2017 |
| Journal | Behav Brain Res | Volume | 322 |
| Issue | Pt B | Pages | 212-222 |
| PubMed ID | 27765672 | Mgi Jnum | J:242650 |
| Mgi Id | MGI:5905946 | Doi | 10.1016/j.bbr.2016.10.023 |
| Citation | Cortez I, et al. (2017) Aged dominant negative p38alpha MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning. Behav Brain Res 322(Pt B):212-222 |
| abstractText | 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 (p38alpha) signaling pathway, we used the dominant negative mouse model for attenuated p38alpha activity (DN-p38alphaAF/+) in which Thr180 and Tyr182 are mutated (T-->A/Y-->F) to prevent phosphorylation activation (DN-p38alphaAF/+) and kinase activity. As a result, aged DN-p38alphaAF/+ 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-p38alphaAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38alpha mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38alphaAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38alphaAF/+ 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-p38alphaAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38alphaAF/+ mice compared to wildtype littermates. Our findings support the notion that p38alpha inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. |
