Oleocanthal ameliorates metabolic and behavioral phenotypes, and pathology in a mouse model of Alzheimer’s disease
Type of DegreePhD Dissertation
Restriction TypeAuburn University Users
MetadataShow full item record
The blood-brain barrier (BBB) healthiness is important to maintain brain homeostasis. The deposition of amyloid-β (Aβ) is one of Alzheimer’s disease’s (AD) causative pathways to induce brain neuronal loss. In addition, AD patients experience BBB dysfunction, and several studies reported correlations between Aβ and BBB dysfunction. The first project aimed to investigate the correlation between BBB healthiness and metabolic and behavioral changes in five AD characteristic-carried (5xFAD) mice as a model for AD as a function of age and pathology. Therefore, in this project, we assessed the mice at 4 and 9 months to represent early and advanced stages of AD for changes in their metabolic and behavioral phenotypes compared with wild-type mice at the same ages. While the pathological characteristics of AD are well established, our understanding of the metabolic and behavioral phenotypes changes, which could be important for early AD diagnosis and staging, continues to be limited. First, we evaluated the metabolic and behavioral alterations by monitoring changes in several parameters, including activity rate, anxiety-like behavior, and sleeping pattern, which are relevant to alterations observed in AD patients. Our findings demonstrated that aging and pathology alter body metabolism and behavior, such as activity rate and sleeping pattern. However, the effect of the pathology on monitored parameters was significantly higher than normal aging, an effect associated with increased Aβ deposition and BBB disruption. In addition, we found a positive correlation between BBB breakdown and increased brain Aβ levels, while a negative correlation was observed between BBB breakdown and sleeping time. In the second project, we aimed to evaluate the effect of repairing the BBB function by targeting the receptor TRPA1 on Aβ pathology and metabolic and behavior phenotypes by the compound oleocanthal (OC) in 5xFAD mice. Previous studies from our laboratory demonstrated the protective and treatment effects of OC against Aβ pathology in AD mice models, an effect that is mediated by enhancing the BBB function. Our studies also showed that OC downregulated the receptor transient receptor potential ankyrin 1 (TRPA1) expression, which upregulated AD. 5xFAD mice (6 months old) were treated with OC at two different doses (1 and 10 mg/kg) for three months by oral gavage. At the end of treatment, mice were assessed for changes in metabolic and behavioral phenotypes, BBB function, BBB endothelium-TRPA1 levels, and Aβ pathology. Our findings demonstrated that 10 mg/kg OC restored the activity rate and sleep pattern to that of the wild-type mice. In addition, our findings demonstrated that OC significantly reduced total and endothelium-TRPA1 and enhanced BBB function. To better clarify the effect of OC on endothelium-TRPA1 expression and function, we performed in vitro studies using the mice brain endothelial cell line bEnd3. Results confirmed TRPA1 expression in bEnd3 cells and that OC treatment reduced Aβ-induced TRPA1 expression and the effect that was associated with reduced intracellular calcium levels. In addition, this effect was associated with enhanced cell-based BBB model integrity and function. Collectively, these findings suggest that OC rectifies the BBB function, at least in part, by reducing endothelium-TRPA1 expression. In conclusion, our findings show that aging and Aβ-related pathology increase activity rate and reduce sleep time, which is associated with BBB dysfunction. Furthermore, restoring the BBB function by OC alters metabolic and behavioral phenotypes to levels similar to wild-type mice.