Abstract
SummaryBlood-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.
Highlights
Circulating factors are known to both enhance[1,2,3,4] and impair[5,6,7] neuronal plasticity and learning in adult mammals
UAG Inhibits Hippocampal Neurogenesis in Adult Mice To assess whether UAG regulates adult neural stem/progenitor cell (NSPC) plasticity in the sub-granular zone (SGZ) of the hippocampus, we analyzed the effect of UAG administered peripherally for 7 days in WT and GOATÀ/À mice.[23]
GOATÀ/À mice lack circulating acyl-ghrelin but have elevated levels of UAG making them ideally suited to assessing the loss of acyl-ghrelin coupled with increased plasma UAG.[31]
Summary
Circulating factors are known to both enhance[1,2,3,4] and impair[5,6,7] neuronal plasticity and learning in adult mammals. The mechanisms underlying these effects are not completely understood Systemic factors such as Growth Differentiation Factor 11 (GDF11)[1] are reported to regulate the neural stem/progenitor cell (NSPC) niche in the adult hippocampus to promote new neuron formation, termed adult hippocampal neurogenesis (AHN), and cognition. Circulating Beta-2 microglobulin (B2M)[6] and eotaxin[5] impair the same niche resulting in reduced neurogenesis and impaired cognitive function. These data demonstrate that the hippocampal neurogenic niche is responsive to systemic factors, even in aged mammals, and suggest that circulating factors act as important modulators of mnemonic function. The suppression of adult neurogenesis was associated with increased neuron loss in 5xFAD, but not wild-type (WT) mice, suggesting a pathophysiological link between impaired AHN and AD progression.[15]
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