title: Neuroprotective effects of incretin mimetics upon chronic endoplasmic
      reticulum (ER) stress
title: implications for novel therapeutic pathways and opportunities in
      Alzheimer's disease
titleType: Subtitle
Creators: name: Panagaki, Theodora
Publisher: name: Lancaster University
Year: 2018

description: 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.