Abstract
Growing evidence suggests that agonists of glucagon-like peptide (GLP-1) receptor exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration, and, recently, a pilot clinical trial of Liraglutide in Alzheimer’s disease patients showed improvements in cerebral glucose consumption that signifies disease progression. However, the exact underlying mechanism of action remains unclear. Chronic endoplasmic reticulum (ER) stress has recently emerged as a mechanism for neuronal injury, rendering it a potent therapeutic target for acute and chronic neurodegenerative disorders. Here, we investigate the neuroprotective effects of Liraglutide along with the signalling network against prolong ER stress and autophagy impairments induced by the non-competitive inhibitor of sarco/ER Ca2+-ATPase, thapsigargin. We show that Liraglutide modulates the ER stress response and elicits ER proteostasis and autophagy machinery homeostasis in human SH-SY5Y neuroblastoma cell line. These effects correlate with resolution of hyper-activity of the antioxidant Nrf2 factor and restoration of the impaired cell viability and proliferation. Mechanistically, Liraglutide engages Akt and signal transducer and activator of transcription 3 (STAT3) signalling to favour adaptive responses and shift cell fate from apoptosis to survival under chronic stress conditions in SH-SY5Y cells.
Highlights
Neuronal injury owing to chronic stress of the endoplasmic reticulum (ER) is increasingly being recognised as a common contributor to amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), ischaemic stroke and traumatic brain injury (TBI)[1–5]
AD features the accumulation of amyloid-β (A β) peptides in the brain, which underlies neuronal dysfunction and cognitive decline
Aβ primarily perturbs the cellular redox status and abnormally increases the amount of calcium that can be released by the ER, triggering ER stress, mitochondrial dysfunction and thereby neuronal toxicity and astrogliosis in vivo[1,4]
Summary
Neuronal injury owing to chronic stress of the endoplasmic reticulum (ER) is increasingly being recognised as a common contributor to amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), ischaemic stroke and traumatic brain injury (TBI)[1–5] Shared among these seemingly dissimilar neurological disorders is the presence of intracellular and/or extracellular conditions that perturb signalling and handling of calcium, protein folding processes and autophagic machinery, generating a vicious circle of irremediable ER stress[1–5]. It is intuitive that therapeutic interventions which resolve UPR and promote a balance between protein generation and degradation crucial for proteostasis may significantly benefit the clinical outcome of acute and chronic neurodegenerative disorders[1,3–5] In this regard, we have focused our research efforts on investigating the restorative effects of the neuroprotective www.nature.com/scientificreports/. Our findings provide additional evidence for the beneficial effects of GLP-1R signalling in neurodegenerative disorders and deepen our understanding of the underlying mechanism
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