A novel derivative of xanomeline improved memory function in aged mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Cui YH
PROVIDER: S-EPMC5552585 | biostudies-other | 2008 Aug
REPOSITORIES: biostudies-other
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Project description:Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways.Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins.CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin.These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.
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Project description:The normal aging process is commonly associated with mild cognitive deficits including memory decline. Previous studies indicate a role of dysregulated messenger ribonucleic acid translation capacity in cognitive defects associated with aging and aging-related diseases, including hyperphosphorylation of eukaryotic elongation factor 2 (eEF2). Phosphorylation of eEF2 by the kinase eEF2K inhibits its activity, hindering general protein synthesis. Here, we sought to determine whether cognitive deficits in aged mice can be improved by genetically deleting eEF2K (eEF2K KO) and consequently reduction of eEF2 phosphorylation. We found that suppression of eEF2K prevented aging-related deficits in novel object recognition memory. Interestingly, deletion of eEF2K did not alter overall protein synthesis in the hippocampus. Ultrastructural analysis revealed increase size and larger active zone lengths of postsynaptic densities in the hippocampus of aged eEF2K KO mice. Biochemical assays showed hippocampal eIF2α hyperphosphorylation in aged eEF2K KO mice, indicating inhibition of translation initiation. Our findings may provide insight into mechanistic understanding and thus development of novel therapeutic strategies for aging-related cognitive decline.
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Project description:BackgroundGrowing evidence has shown that obesity is associated with poor neurocognitive outcomes. Bariatric surgery has been shown to be an effective intervention for morbid obesity and can result in improvement of many co-morbid medical conditions that are associated with cognitive dysfunction. The effects of bariatric surgery on cognition are unknown.MethodsWe performed a prospective study total of 150 subjects (109 bariatric surgery patients enrolled in the Longitudinal Assessment of Bariatric Surgery project and 41 obese control subjects who had not undergone bariatric surgery). These 150 subjects completed a cognitive evaluation at baseline and at 12 weeks of follow-up. The demographic, medical, and psychosocial information was also collected to elucidate the possible mechanisms of change.ResultsMany bariatric surgery patients exhibited impaired performance on cognitive testing at baseline (range 4.6-23.9%). However, the surgery patients were no more likely to exhibit a decline on ?2 cognitive tests at 12 weeks of follow-up than were the obese controls [12.84% versus 23.26%; chi-square (1) = 2.51, P = .11]. Group comparisons using repeated measures multivariate analysis of variance showed that the surgery patients had improved memory performance at 12 weeks of follow-up [? = .86, F(4, 147) = 5.88, P <.001]; however, the memory performance of the obese controls had actually declined. Regression analyses showed that the surgery patients without hypertension had better short delay recall at 12 weeks than those with hypertension [? = .31, P = .005], although the other demographic and medical variables were largely unrelated to the test performance.ConclusionThe present results suggest that cognitive impairment is common in bariatric surgery patients, although these deficits might be at least partly reversible. Future studies are needed to clarify the underlying mechanisms, in particular, longitudinal studies using neuroimaging and blood markers.
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Project description:The mammalian hippocampus shows marked decline in function with aging across many species, including humans and laboratory rodent models. This decline frequently manifests in memory impairments that occur even in the absence of dementia pathology. In humans, a number of factors correlate with preserved hippocampal memory in aging, such as exercise, cognitive stimulation and number of social ties. While interventional studies and animal models clearly indicate that exercise and cognitive stimulation lead to hippocampal preservation, there is relatively little research on whether a decline in social ties leads to cognitive decline or vice versa. Even in animal studies of environmental enrichment in aging, the focus typically falls on physical enrichment such as a rotating cast of toys, rather than the role of social interactions. The present studies investigated the hypothesis that a greater number of social ties in aging mice would lead to improved hippocampal function. Aged, female C57/Bl6 mice were housed for 3 months in pairs or large groups (7 mice per cage). Group-housed mice showed greater novel object location memory and stronger preference for a spatial navigation strategy in the Barnes maze, though no difference in escape latency, compared to pair-housed mice. Group-housed mice did not differ from pair-housed mice in basal corticosterone levels or adult hippocampal neurogenesis. Group-housed mice did, however, show reduced numbers of Iba1/CD68+ microglia in the hippocampus. These findings suggest that group housing led to better memory function and reduced markers of neuroinflammation in aged mice. More broadly, they support a causative link between social ties and hippocampal function, suggesting that merely having a larger social network can positively influence the aging brain. Future research should address the molecular mechanisms by which a greater number of social ties alters hippocampal function.
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