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

Lookup NU author(s): Dr Fionnuala Johnston, Dr Mario Siervo, Professor David BurnORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020 The Author(s)The gut-hormone acyl-ghrelin (AG) is known to promote adult hippocampal neurogenesis. Hornsby et al. combine in vitro and in vivo rodent models, alongside analysis of human plasma, to show that unacylated-ghrelin (UAG) impairs neurogenesis and that the circulating AG:UAG ratio is reduced in Parkinson's dementia.© 2020 The Author(s)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.

Publication metadata

Author(s): Hornsby AKE, Buntwal L, Carisi MC, Santos VV, Johnston F, Roberts LD, Sassi M, Mequinion M, Stark R, Reichenbach A, Lockie SH, Siervo M, Howell O, Morgan AH, Wells T, Andrews ZB, Burn DJ, Davies JS

Publication type: Article

Publication status: Published

Journal: Cell Reports Medicine

Year: 2020

Volume: 1

Issue: 7

Online publication date: 20/10/2020

Acceptance date: 16/09/2020

Date deposited: 12/01/2021

ISSN (electronic): 2211-1247

Publisher: Cell Press

URL: https://doi.org/10.1016/j.xcrm.2020.100120

DOI: 10.1016/j.xcrm.2020.100120

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