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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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first_indexed 2021-12-06T12:28:31Z
last_indexed 2021-12-07T04:15:51Z
id cronfa58915
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spelling 2021-12-06T13:00:16.1027166 v2 58915 2021-12-06 Characterisation of the ghrelinergic system in human models of neurodegenerative diseases 5985106c90247dbb94f6589ac8317cc2 MARIA CARISI' MARIA CARISI' true false 2021-12-06 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. E-Thesis Swansea 6 12 2021 2021-12-06 10.23889/SUthesis.58915 COLLEGE NANME COLLEGE CODE Swansea University Davies, Jeffrey S. ; Morgan, Alwena H. Doctoral Ph.D BRACE 2021-12-06T13:00:16.1027166 2021-12-06T12:25:22.4901442 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine MARIA CARISI' 1 58915__21805__66159462c5df4ebc8c1edda019cf6840.pdf Carisi_Maria_C_PhD_Thesis_Final_Redacted_Signature.pdf 2021-12-06T12:35:46.3399951 Output 7846958 application/pdf E-Thesis – open access true Copyright: The author, Maria C. Carisì, 2021. true eng
title Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
spellingShingle Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
MARIA CARISI'
title_short Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
title_full Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
title_fullStr Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
title_full_unstemmed Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
title_sort Characterisation of the ghrelinergic system in human models of neurodegenerative diseases
author_id_str_mv 5985106c90247dbb94f6589ac8317cc2
author_id_fullname_str_mv 5985106c90247dbb94f6589ac8317cc2_***_MARIA CARISI'
author MARIA CARISI'
author2 MARIA CARISI'
format E-Thesis
publishDate 2021
institution Swansea University
doi_str_mv 10.23889/SUthesis.58915
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description 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.
published_date 2021-12-06T04:15:49Z
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