Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK.
Biomedical Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia.
Cell Rep Med. 2020 Oct 20;1(7):100120. doi: 10.1016/j.xcrm.2020.100120.
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 was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational 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.
血液源性因子调节哺乳动物成年海马体神经发生和认知。我们报告称，通过药理学和遗传学方法提高循环未酰化 ghrelin (UAG) 水平会减少小鼠海马体神经发生和可塑性。缺乏酰化 ghrelin (AG) 但 UAG 水平较高的 ghrelin-O-酰基转移酶缺失 (GOAT) 小鼠表现出空间记忆障碍，而酰化 ghrelin 则可挽救该障碍。酰化 ghrelin 介导的神经发生依赖于非细胞自主的 BDNF 信号，而 UAG 抑制了该信号。这些发现表明 ghrelin 的翻译后修饰对小鼠的神经发生和记忆很重要。为了确定在人类中的相关性，我们分析了帕金森病 (PD) 患者中被诊断为痴呆 (PDD)、认知正常的 PD 患者和对照组的循环 AG:UAG。值得注意的是，仅在 PDD 患者中降低了血浆 AG:UAG。海马 ghrelin 受体表达保持不变；然而，GOAT 细胞数量在 PDD 中减少。我们将 UAG 鉴定为调节海马体依赖性可塑性和空间记忆的因子，并将 AG:UAG 鉴定为痴呆症的潜在循环诊断生物标志物。
