Brain mechanism underlying strong neuroplastic benefit by a combined strategy with light exercise and astaxanthin supplementation

利用RIKEN开发的阿尔茨海默病（AD）模型（APPNL-G-F小鼠），该模型显示了人类AD患者的病理表型，我们旨在研究轻强度运动（LE）和虾青素（ASX）摄入的长期联合干预是否促进AD中海马依赖的神经可塑性和随后的认知增强，从而阐明脑源性瘦素（LEP）作为潜在分子靶点的作用。我们研究了年龄匹配野生型小鼠的病理表型和LEP的表达，作为对照，LE处理的APPNL-G-F和APPNL-G-F以及LE和ASX联合处理的APPNL-G-F小鼠。结果表明，LE和ASX联合治疗可逆转Morris水迷宫实验中空间记忆受损的病理表型以及海马中淀粉样蛋白β-肽的积累和LEP的过表达。此外，我们发现LE和ASX联合治疗对APPNL-G-F小鼠海马神经发生和BDNF表达有协同改善作用。然而，我们仍然面临着越来越多的争论，即在大脑中检测到的LEP来源是否真的是大脑。为了揭示LEP的起源，我们建立了原位杂交技术，到目前为止，我们在这方面取得了很大进展，并初步成功地标记了海马CA2/3区LEP mRNA。还有很多问题有待解决，但这些发现将为阿尔茨海默病患者LEP介导的海马神经可塑性提供新的见解。

Using the Alzheimer’s disease (AD) model (APPNL-G-F mice) developed by the RIKEN, which demonstrates pathological phenotypes of human patients with AD, we aimed to investigate whether a long-term combined intervention of light-intensity exercise (LE) and astaxanthin (ASX) intake facilitate the hippocampal-dependent neural plasticity and subsequent cognitive enhancement in AD, thereby elucidating the role of brain-genic leptin (LEP) as a potential molecule target. We investigated pathological phenotypes and LEP expression shown in age-matched wild-type mice as a control, APPNL-G-F and APPNL-G-F treated with LE, and APPNL-G-F mice combined-treated with LE and ASX. It revealed that the pathological phenotypes featured by the impaired spatial memory in Morris water maze test and the accumulation of amyloid β-peptide as well as the overexpression of LEP in the hippocampus, might be reversed by combined treatment of LE and ASX. Furthermore, we found the synergistic improvement in the hippocampal neurogenesis and BDNF expression by combined treatment of LE and ASX of APPNL-G-F mice. However, we are still confronting the growing debates about whether the source of LEP detected in the brain is actually the brain. To reveal the origin of LEP, we established an in situ hybridization technique, and as of now, we have made great progress on this and tentatively succeeded in labeling LEP mRNA in hippocampal CA2/3 region. There is a lot to unravel, but these findings will give a new insight into hippocampal neuroplasticity mediated by LEP in patients with AD.