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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, Alwena Morgan, Timothy Wells, Zane B. Andrews, David J. Burn, Jeffrey Davies
Cell Reports Medicine, Volume: 1, Issue: 7, Start page: 100120
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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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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.
ghrelin; GOAT; acyl-ghrelin; unacylated-ghrelin; AG:UAG; adult hippocampal neurogenesis; memory; BDNF; Parkinson disease dementia; biomarker
Swansea University Medical School