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Title: Neuroprotective effects of incretin mimetics upon chronic endoplasmic reticulum (ER) stress : implications for novel therapeutic pathways and opportunities in Alzheimer's disease
Author: Panagaki, Theodora
ISNI:       0000 0004 7426 3292
Awarding Body: Lancaster University
Current Institution: Lancaster University
Date of Award: 2018
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Growing evidence suggests that incretin mimetics exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration. In a recent pilot clinical trial, Liraglutide rescued the decline of the cerebral glucose consumption in Alzheimer’s disease (AD) patients, signifying improved energy metabolism in brain areas previously correlated with cognitive decline and disease progression. However, the exact underlying mechanism of action remains unclear. Chronic endoplasmic reticulum (ER) stress has emerged as a hub for the aberrant proteostasis underlying the onset and progression of neuronal degeneration that renders it a pivotal therapeutic target for AD. Herein, I examined the neuroprotective effects of Liraglutide along with the signalling network against the persistent and calcium-dependent ER stress in the human proliferating SH-SY5Y neuroblastoma cells. I report that Liraglutide modulated the ER stress response and elicited ER proteostasis and autophagy machinery homeostasis to restore the hyperactivity of the antioxidant Nrf2 factor and halt the impaired cell viability and proliferation. Mechanistically, Liraglutide engaged the Akt pathway and normalised the signal transducer and activator of transcription 3 (STAT3) activity to favour adaptive responses and shift cell fate towards survival under chronic stress conditions. These findings have motivated me to replicate the phenotype in human post-mitotic neurones from the LUHMES cell line. I have further addressed the neuroprotective and restorative effects of a novel dual incretin against the chronic and calcium-dependent ER stress. Novel dual incretin analogues have recently been developed and have displayed superior anti-hyperglycaemic and insulinotropic efficacy compared to Liraglutide, rendering them potent candidates for the treatment of diabetes mellitus type 2. Consistently, I showed that the chronic incretin treatment modulated the ER stress response and promoted homeostasis of the ER chaperones and autophagy machinery to rescue the excessive synapse damage and death of post-mitotic neurones. The incretin mimetics restored the suppressed Akt and signal transducer and activator of transcription 3 (STAT3) signalling to resolve the impaired activity of the antioxidant Nrf2 factor and confer trophic signals for neuronal repair following chronically persistent ER stress. Finally, I have assessed the effects of the dual incretin in the APPswe/PS1∆E9 mouse model for AD at the age of 10 months and compared them to Liraglutide and the glucosedependent insulinotropic peptide (GIP) mono-therapy. Once-a-day intraperitoneal administration of 25 nmol kg−1 of the dual incretin for two months halted the spatial cognitive decline and synapse damage of this murine model. It remarkably decreased the plaque deposition and gliosis over the APPswe/PS1∆E9 mouse cortex and hippocampus too. The attenuation of the AD-like pathology reflected the resolution of ER stress and restoration of autophagy impairments, both lying downstream of the rectified Akt signalling. Collectively, the findings presented in the current thesis endorsed the beneficial effects of the incretin signalling in the neuronal degeneration management and further deepened our understanding of the incretin neuropharmacology.
Supervisor: Holscher, Christian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral