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

Hornsby, A. K. E.; Santos, V. V.; Johnston, F.; Roberts, L. D.; Stark, R.; Reichenbach, A.; Siervo, M.; Wells, T.; Andrews, Z. B.; Burn, D. J.; Davies, J. S.

doi:10.1101/259333

bioRxiv · 10.1101/259333

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

Hornsby, A. K. E.·Santos, V. V.·Johnston, F.·Roberts, L. D.·Stark, R.·Reichenbach, A.·Siervo, M.·Wells, T.·Andrews, Z. B.·Burn, D. J.·Davies, J. S.

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Abstract

Blood-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 post-translational 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 Parkinsons 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.\n\nHighlightsO_LICirculating UAG impairs markers of neurogenesis and plasticity\nC_LIO_LIGOAT-/-mice have impaired neurogenesis and spatial memory\nC_LIO_LICirculating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT-/-mice\nC_LIO_LICirculating AG:UAG ratio is reduced in Parkinsons disease dementia\nC_LI

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Hornsby, A. K. E., Santos, V. V., Johnston, F., Roberts, L. D., Stark, R., Reichenbach, A., Siervo, M., Wells, T., Andrews, Z. B., Burn, D. J., Davies, J. S.. 2018-02-05. Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson’s disease dementia. https://doi.org/10.1101/259333

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