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Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans

Amanda Hornsby, Luke Buntwal, Carla Carisi, Vanessa V. Santos, Fionnuala Johnston, Luke Roberts, Martina Sassi, Mathieu Mequinion, Romana Stark, Alex Reichenbach, Sarah H. Lockie, Mario Siervo, Owain Howell Orcid Logo, Alwena Morgan Orcid Logo, Timothy Wells, Zane B. Andrews, David J. Burn, Jeffrey Davies Orcid Logo

Cell Reports Medicine, Volume: 1, Issue: 7, Start page: 100120

Swansea University Authors: Amanda Hornsby, Luke Buntwal, Carla Carisi, Luke Roberts, Martina Sassi, Owain Howell Orcid Logo, Alwena Morgan Orcid Logo, Jeffrey Davies Orcid Logo

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Abstract

Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin...

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Published in: Cell Reports Medicine
ISSN: 2666-3791
Published: Elsevier BV 2020
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spelling 2020-12-30T17:09:20.0869901 v2 55678 2020-11-16 Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans 52a586048b9cb0543fe0f3e112e345c3 Amanda Hornsby Amanda Hornsby true false 17487859981a64bd23785039c5f95f0d Luke Buntwal Luke Buntwal true false b9eb37d84630e887855f17bdf94b6708 Carla Carisi Carla Carisi true false 22576ee8492628137b76a5b8cb68a384 Luke Roberts Luke Roberts true false 73844ea9bb96bff6f83ffeffa8f64a49 Martina Sassi Martina Sassi true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 9ea39c3d0935c897cb9fcd3ba550af71 0000-0002-3441-5357 Alwena Morgan Alwena Morgan true false 2cb3d1d96a7870a84d2f758e865172e6 0000-0002-4234-0033 Jeffrey Davies Jeffrey Davies true false 2020-11-16 FGMHL Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT/) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia. Journal Article Cell Reports Medicine 1 7 100120 Elsevier BV 2666-3791 ghrelin; GOAT; acyl-ghrelin; unacylated-ghrelin; AG:UAG; adult hippocampal neurogenesis; memory; BDNF; Parkinson disease dementia; biomarker 20 10 2020 2020-10-20 10.1016/j.xcrm.2020.100120 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2020-12-30T17:09:20.0869901 2020-11-16T18:00:26.0357097 Swansea University Medical School Medicine Amanda Hornsby 1 Luke Buntwal 2 Carla Carisi 3 Vanessa V. Santos 4 Fionnuala Johnston 5 Luke Roberts 6 Martina Sassi 7 Mathieu Mequinion 8 Romana Stark 9 Alex Reichenbach 10 Sarah H. Lockie 11 Mario Siervo 12 Owain Howell 0000-0003-2157-9157 13 Alwena Morgan 0000-0002-3441-5357 14 Timothy Wells 15 Zane B. Andrews 16 David J. Burn 17 Jeffrey Davies 0000-0002-4234-0033 18 55678__18674__034ac5116f144be6b7513fa7514dd92c.pdf Hornsby et al.2020.pdf 2020-11-16T18:05:54.8266012 Output 8114380 application/pdf Version of Record true ©2020 The Author(s). This is an open access article under the CC BY license true eng http://creativecommons.org/licenses/by/4.0/
title Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
spellingShingle Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
Amanda Hornsby
Luke Buntwal
Carla Carisi
Luke Roberts
Martina Sassi
Owain Howell
Alwena Morgan
Jeffrey Davies
title_short Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
title_full Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
title_fullStr Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
title_full_unstemmed Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
title_sort Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
author_id_str_mv 52a586048b9cb0543fe0f3e112e345c3
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author_id_fullname_str_mv 52a586048b9cb0543fe0f3e112e345c3_***_Amanda Hornsby
17487859981a64bd23785039c5f95f0d_***_Luke Buntwal
b9eb37d84630e887855f17bdf94b6708_***_Carla Carisi
22576ee8492628137b76a5b8cb68a384_***_Luke Roberts
73844ea9bb96bff6f83ffeffa8f64a49_***_Martina Sassi
58c995486fc93a242b987640b692db8c_***_Owain Howell
9ea39c3d0935c897cb9fcd3ba550af71_***_Alwena Morgan
2cb3d1d96a7870a84d2f758e865172e6_***_Jeffrey Davies
author Amanda Hornsby
Luke Buntwal
Carla Carisi
Luke Roberts
Martina Sassi
Owain Howell
Alwena Morgan
Jeffrey Davies
author2 Amanda Hornsby
Luke Buntwal
Carla Carisi
Vanessa V. Santos
Fionnuala Johnston
Luke Roberts
Martina Sassi
Mathieu Mequinion
Romana Stark
Alex Reichenbach
Sarah H. Lockie
Mario Siervo
Owain Howell
Alwena Morgan
Timothy Wells
Zane B. Andrews
David J. Burn
Jeffrey Davies
format Journal article
container_title Cell Reports Medicine
container_volume 1
container_issue 7
container_start_page 100120
publishDate 2020
institution Swansea University
issn 2666-3791
doi_str_mv 10.1016/j.xcrm.2020.100120
publisher Elsevier BV
college_str Swansea University Medical School
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hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
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description Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT/) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.
published_date 2020-10-20T04:10:52Z
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