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

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

Cell Reports Medicine (Oct 2020)

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

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

Affiliations

Amanda K.E. Hornsby: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Luke Buntwal: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Maria Carla Carisi: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Vanessa V. Santos: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
Fionnuala Johnston: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Luke D. Roberts: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Martina Sassi: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Mathieu Mequinion: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
Romana Stark: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
Alex Reichenbach: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
Sarah H. Lockie: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
Mario Siervo: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; School of Life Sciences, Queen's Medical Centre, The University of Nottingham Medical School, Nottingham NG7 2UH, UK
Owain Howell: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Alwena H. Morgan: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK
Timothy Wells: School of Biosciences, Cardiff University, Cardiff, UK
Zane B. Andrews: Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia
David J. Burn: Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Jeffrey S. Davies: Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK; Corresponding author

Journal volume & issue: Vol. 1, no. 7
p. 100120

Abstract

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Summary: 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 in Cell Reports Medicine

ISSN: 2666-3791 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General)
Website: https://www.cell.com/cell-reports-medicine

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