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

Autor: Romana Stark, Owain W. Howell, Fionnuala Johnston, Mathieu Méquinion, David J. Burn, Martina Sassi, Luke D. Roberts, Zane B. Andrews, Alexander Reichenbach, Vanessa V. Santos, Luke Buntwal, Amanda K. E. Hornsby, Timothy N. C. Wells, Jeffrey S. Davies, Mario Siervo, Sarah Kathleen Haas Lockie, Alwena H. Morgan, Maria Carla Carisi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Cell number
Parkinson disease dementia
Regulator
Hippocampal formation
Hippocampus
memory
Mice
Cognition
GOAT
Spatial Memory
Mice
Knockout
Neurons
lcsh:R5-920
Neuronal Plasticity
digestive
oral
and skin physiology
Neurogenesis
Parkinson Disease
ghrelin
biomarker
Biomarker (medicine)
Female
Ghrelin
Supranuclear Palsy
Progressive
lcsh:Medicine (General)
Signal Transduction
medicine.medical_specialty
Primary Cell Culture
Unacylated ghrelin
Article
General Biochemistry
Genetics and Molecular Biology
Internal medicine
medicine
Animals
Humans
Dementia
acyl-ghrelin
business.industry
Brain-Derived Neurotrophic Factor
Membrane Proteins
medicine.disease
adult hippocampal neurogenesis
Rats
Mice
Inbred C57BL
unacylated-ghrelin
Disease Models
Animal
BDNF
Endocrinology
Gene Expression Regulation
AG:UAG
business
Acyltransferases
Zdroj: Cell Reports Medicine, Vol 1, Iss 7, Pp 100120-(2020)
Cell Reports. Medicine
ISSN: 2666-3791
Popis: 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.
Graphical Abstract
Highlights Circulating unacylated-ghrelin (UAG) reduces hippocampal neurogenesis Circulating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT−/− mice UAG blocks the AG induced survival of newborn hippocampal cells Plasma AG:UAG and hippocampal GOAT+ cells are reduced in Parkinson’s dementia
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.
Databáze: OpenAIRE
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