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Characterisation of the ghrelinergic system in human models of neurodegenerative diseases / MARIA CARISI'

Swansea University Author: MARIA CARISI'

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DOI (Published version): 10.23889/SUthesis.58915

Abstract

Calorie restriction (CR) has well established neuroprotective properties across species and is known to prevent cognitive deficits in several mouse models and in aged humans. Our group and others have shown that CR beneficial effects are dependent on the circulating hormone acyl-ghrelin (AG), that p...

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Published: Swansea 2021
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Davies, Jeffrey S. ; Morgan, Alwena H.
URI: https://cronfa.swan.ac.uk/Record/cronfa58915
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Abstract: Calorie restriction (CR) has well established neuroprotective properties across species and is known to prevent cognitive deficits in several mouse models and in aged humans. Our group and others have shown that CR beneficial effects are dependent on the circulating hormone acyl-ghrelin (AG), that promotes hippocampal memory function and protects against neurodegeneration in rodents. Indeed, ghrelin knockout (KO) mice show defects in memory task performance and plasma ghrelin levels are significantly reduced in aged humans. Because of its connection to memory and ageing, AG has been studied in mouse models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the two most common causes of dementia in the aged population. However, very few of these studies have been performed in human models. This project aimed to determine the expression of key regulatory proteins of the ghrelin pathway in the young and aged healthy human brain, as well as brain of AD and PD patients, combining immunohistochemistry, RNA in situ hybridization, and molecular biology. My findings show that the key enzymes of the ghrelinergic axis – GHS-R1a, GOAT and APT1 – are highly expressed in the aged healthy human hippocampus, but their expression level is impaired in PD with dementia . Further studies are needed to determine a potential correlation between the activity of ghrelin in the brain and the level of cognitive impairment and dementia. On the contrary, very little difference is observed between early and late stage of AD, suggesting that the ghrelinergic system may not be impaired in these patients. The second aim was to characterize the effects of AG on a human neuronal cell line treated with rotenone or amyloid-β oligomers (AβOs) to simulate oxidative stress from PD and AD, respectively. Using confocal microscopy and molecular biology techniques, I assessed neuronal cell death and mitochondrial function and reported significant mitochondrial toxicity in these models, that worsen by chronic pre-treatment with the inactive form of AG, unacylated ghrelin (UAG). Ultimately, this project supports the ghrelinergic axis as a potential target for future studies aiming to identify treatments to limit the progression of dementia in humans.
College: Swansea University Medical School