Abstract
Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1KO mice) have a significant reduction in lifespan, exhibit many phenotypes of accelerated aging, and have high levels of oxidative stress in various tissues. Age-associated cognitive decline is a hallmark of aging and the increase in oxidative stress/damage with age is one of the mechanisms proposed for cognitive decline with age. Therefore, the goal of this study was to determine if Sod1KO mice exhibit an accelerated loss in cognitive function similar to that observed in aged animals. Cognition was assessed in Sod1KO and wild type (WT) mice using an automated home-cage testing apparatus (Noldus PhenoTyper) that included an initial discrimination and reversal task. Comparison of the total distance moved by the mice during light and dark phases of the study demonstrated that the Sod1KO mice do not show a deficit in movement. Assessment of cognitive function showed no significant difference between Sod1KO and WT mice during the initial discrimination phase of learning. However, during the reversal task, Sod1KO mice showed a significantly greater number of incorrect entries compared to WT mice indicating a decline in cognition similar to that observed in aged animals. Markers of oxidative stress (4-Hydroxynonenal, 4-HNE) and neuroinflammation [proinflammatory cytokines (IL6 and IL-1β) and neuroinflammatory markers (CD68, TLR4, and MCP1)] were significantly elevated in the hippocampus of male and female Sod1KO compared to WT mice. This study provides important evidence that increases in oxidative stress alone are sufficient to induce neuroinflammation and cognitive dysfunction that parallels the memory deficits seen in advanced aging and neurodegenerative diseases.
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Acknowledgements
This work was supported by NIH/NIA R01 AG059718, Oklahoma Center for the Advancement of Science and Technology research grant (HR18-053) and Presbyterian Health Foundation (OUHSC) Seed grant to Dr. Sathyaseelan S Deepa; National Institute on Aging K99 AG056662 to Dr. Sreemathi Logan; T32 AG052363 and R01 NS056218 to Dr. William Sonntag; R01 AG057424 to Drs. William Sonntag and Arlan Richardson. The research was also partially supported by grants awarded to Dr. Arlan Richardson from the National Institute on Aging (P01AG020591, R01AG045693).
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Logan, S., Royce, G.H., Owen, D. et al. Accelerated decline in cognition in a mouse model of increased oxidative stress. GeroScience 41, 591–607 (2019). https://doi.org/10.1007/s11357-019-00105-y
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DOI: https://doi.org/10.1007/s11357-019-00105-y