Aging, adipokines and Alzheimer's disease : exploring the neuroprotective effects of leptin and cholecystokinin

Abstract

No current theory of ageing presents a full explanation of the ageing processes. This thesis posits focus should be on the ageing endocrine system both in healthy and pathological ageing, such as Alzheimer’s disease (AD), and its treatment. Two hormones were investigated in the context of AD as potential therapeutics. Leptin has demonstrated neuroprotective and disease modifying effects both in vitro and in vivo, however it has wide ranging actions that lead to off‐target effects. This thesis aimed to show the bioactive leptin peptide leptin116‐130, which may avoid these side‐effects, can demonstrate the beneficial effects of leptin. Leptin116‐130 was found to mirror the neuroprotective and cognitive enhancing effects of leptin, and hence has potential for an AD therapeutic. Cholecystokinin (CCK) receptor 1 (CCK1R) agonism by A71623 was also investigated as CCK1R deficiency causes memory impairments in rats and in humans higher CCK levels correlated with decreased risk of AD. A71623 had neuroprotective effects, decreased tau phosphorylation and modulated nitric oxide. Demonstrating the potential to have disease modifying effects. Finally, as leptin and CCK have previously been shown to have synergistic action, and other co‐treatments in diseases produce effects with lower concentrations, reduced side‐effects and wider scope of action this therapeutic strategy was explored. A71623 co‐ treatment with leptin116‐130 but not leptin showed promising neuroprotective effects. Changes in these drugs receptors, ObR and CCK1R, studied using the ageing SHSY‐5Y model, rat cortex and healthy and cognitive decline syndrome cats, show co‐treatment may generate better long‐term efficacy due to differing changes in receptor expression by brain region both with age and onset of an AD‐like disease. These results demonstrate for the first time the promise of leptin116‐130 and CCK1R agonism in the treatment of AD and as such greater understanding of the endocrine system with age may lead to better treatments for age‐related diseases.