E-Thesis 716 views
Investigating the role of the ghrelin axis in cognitive decline and dementia / MARTINA SASSI
Swansea University Author: MARTINA SASSI
DOI (Published version): 10.23889/SUthesis.57625
Abstract
Ghrelin is a 28-amino acid hormone that is generated in a wide number of tissues. Its active form, acyl-ghrelin is able to bind to its receptor GHS-R and exert a variety of functions. In the brain, acyl-ghrelin has been associated with neuroprotection, improved memory and adult hippocampal neurogene...
| Published: |
Swansea
2021
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|---|---|
| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Davies, Jeffrey S. ; Morgan, Alwena H. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa57625 |
| first_indexed |
2021-08-17T13:32:34Z |
|---|---|
| last_indexed |
2021-08-18T03:22:17Z |
| id |
cronfa57625 |
| recordtype |
RisThesis |
| fullrecord |
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| spelling |
2021-08-17T15:21:27.9407244 v2 57625 2021-08-17 Investigating the role of the ghrelin axis in cognitive decline and dementia 2d3cd1b9434618a94e868b072d29f729 MARTINA SASSI MARTINA SASSI true false 2021-08-17 Ghrelin is a 28-amino acid hormone that is generated in a wide number of tissues. Its active form, acyl-ghrelin is able to bind to its receptor GHS-R and exert a variety of functions. In the brain, acyl-ghrelin has been associated with neuroprotection, improved memory and adult hippocampal neurogenesis (AHN). However, the mechanisms controlling acyl-ghrelin-mediated AHN are still unknown. To elucidate this process, different markers of neurogenesis were assessed in a mouse model in which GHS-R+ neurones were ablated specifically from the rostral DG of the hippocampus (rDG), showing that rDG GHS-R+ neurones are essential for maintaining AHN. Acyl-ghrelin has also been shown to prevents the damage caused by neurodegeneration, at least in young animal models of disease. In this thesis, we demonstrated that in the geriatric Tg2576 mouse model of Alzheimer’s disease, acyl-ghrelin maintained an effect on β-amyloid (Aβ) plaques in the hippocampus, promoting a reduction of the Aβ plaques size in AD-like mouse model compared to WT mice. Collectively, research findings highlight the importance of circulating acyl-ghrelin in the brain. However, ghrelin exists in two distinct forms and acyl-ghrelin can be enzymatically modified to the ‘inactive' unacylated-ghrelin (UAG) by acyl-protein thioesterase 1 (APT1). Preventing APT1 mediated de-acylation and increasing acyl-ghrelin bio-availability may prevent the damage caused by neurodegeneration. Unpublished data from our group suggest that PalmostatinB, an APT1 inhibitor, increases levels of acyl-ghrelin in macrophage cells (that naturally produce ghrelin). Therefore, this and other APT1 inhibitors may be considered possible therapeutic agents for the treatment of cognitive decline and diseases associated with dementia. We confirmed that, among several APT1 inhibitors, PalmostatinB is able to increase the level of acyl-ghrelin in vitro. However, further research is warranted into APT1 inhibitors as a novel therapeutic approach to treating cognitive decline and dementia. Together, the data in this thesis support a role for the ghrelinergic system components in modulating brain functions. E-Thesis Swansea 30 1 2021 2021-01-30 10.23889/SUthesis.57625 COLLEGE NANME COLLEGE CODE Swansea University Davies, Jeffrey S. ; Morgan, Alwena H. Doctoral Ph.D 2021-08-17T15:21:27.9407244 2021-08-17T14:30:11.1345543 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine MARTINA SASSI 1 Under embargo Under embargo 2021-08-17T14:50:18.6023740 Output 5847127 application/pdf E-Thesis – open access true 2026-08-01T00:00:00.0000000 Copyright: The author, Martina Sassi, 2021. true eng |
| title |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| spellingShingle |
Investigating the role of the ghrelin axis in cognitive decline and dementia MARTINA SASSI |
| title_short |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| title_full |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| title_fullStr |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| title_full_unstemmed |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| title_sort |
Investigating the role of the ghrelin axis in cognitive decline and dementia |
| author_id_str_mv |
2d3cd1b9434618a94e868b072d29f729 |
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2d3cd1b9434618a94e868b072d29f729_***_MARTINA SASSI |
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MARTINA SASSI |
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MARTINA SASSI |
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E-Thesis |
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2021 |
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Swansea University |
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10.23889/SUthesis.57625 |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine |
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| description |
Ghrelin is a 28-amino acid hormone that is generated in a wide number of tissues. Its active form, acyl-ghrelin is able to bind to its receptor GHS-R and exert a variety of functions. In the brain, acyl-ghrelin has been associated with neuroprotection, improved memory and adult hippocampal neurogenesis (AHN). However, the mechanisms controlling acyl-ghrelin-mediated AHN are still unknown. To elucidate this process, different markers of neurogenesis were assessed in a mouse model in which GHS-R+ neurones were ablated specifically from the rostral DG of the hippocampus (rDG), showing that rDG GHS-R+ neurones are essential for maintaining AHN. Acyl-ghrelin has also been shown to prevents the damage caused by neurodegeneration, at least in young animal models of disease. In this thesis, we demonstrated that in the geriatric Tg2576 mouse model of Alzheimer’s disease, acyl-ghrelin maintained an effect on β-amyloid (Aβ) plaques in the hippocampus, promoting a reduction of the Aβ plaques size in AD-like mouse model compared to WT mice. Collectively, research findings highlight the importance of circulating acyl-ghrelin in the brain. However, ghrelin exists in two distinct forms and acyl-ghrelin can be enzymatically modified to the ‘inactive' unacylated-ghrelin (UAG) by acyl-protein thioesterase 1 (APT1). Preventing APT1 mediated de-acylation and increasing acyl-ghrelin bio-availability may prevent the damage caused by neurodegeneration. Unpublished data from our group suggest that PalmostatinB, an APT1 inhibitor, increases levels of acyl-ghrelin in macrophage cells (that naturally produce ghrelin). Therefore, this and other APT1 inhibitors may be considered possible therapeutic agents for the treatment of cognitive decline and diseases associated with dementia. We confirmed that, among several APT1 inhibitors, PalmostatinB is able to increase the level of acyl-ghrelin in vitro. However, further research is warranted into APT1 inhibitors as a novel therapeutic approach to treating cognitive decline and dementia. Together, the data in this thesis support a role for the ghrelinergic system components in modulating brain functions. |
| published_date |
2021-01-30T04:56:47Z |
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1856984692411072512 |
| score |
11.096068 |