Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson's disease dementia

Abstract

Highlights• Circulating UAG impairs markers of neurogenesis and plasticity• GOAT -/-mice have impaired neurogenesis and spatial memory• Circulating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT -/-mice • Circulating AG:UAG ratio is reduced in Parkinson's disease dementia AbstractBlood-borne factors regulate adult hippocampal neurogenesis (AHN) and cognition in mammals, albeit via mechanisms that are poorly understood. 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 GOAT -/-mice that lack acyl-ghrelin (AG) but have high levels of UAG, were rescued by treatment with AG. This unexpected finding suggests that the posttranslational acylation of ghrelin is an important modulator of neurogenesis and memory in adult mammals. To determine whether this paradigm is relevant to humans we analysed circulating AG:UAG levels in Parkinson's disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients and healthy controls. Uniquely, the ratio of plasma AG:UAG was reduced in the PDD cohort and correlated with cognitive performance. Our results identify UAG as a novel regulator of neurogenesis and cognition, and AG:UAG as a circulating diagnostic biomarker of dementia. The findings extend our understanding of adult brain plasticity regulation by circulating factors and suggest that manipulating the post-translational acylation of plasma ghrelin may offer therapeutic opportunities to ameliorate cognitive decline.

Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis

“…All immunohistochemical (IHC) protocols used within this thesis are published and generally used protocols of the free-floating method of IHC staining (Hornsby et al, 2016(Hornsby et al, , 2018Kent et al, 2015).…”

“…n = 5-6 mice/group. Main 10x magnification images, scale bar = 2100µm, inset 40ximages scale bar = 50µm(Hornsby et al, 2018).…”