Liu Enjie, Zhou Qiuzhi, Xie Ao-Ji, Li Mengzhu, Zhang Shujuan, Huang Hezhou, Liuyang Zhenyu, Wang Yali, Liu Bingjin, Li Xiaoguang, Sun Dongsheng, Wei Yuping, Wang Xiaochuan, Wang Qun, Ke Dan, Yang Xifei, Yang Ying, Wang Jian-Zhi
1Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.
4Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.
Transl Neurodegener. 2019 Mar 5;8:8. doi: 10.1186/s40035-019-0149-9. eCollection 2019.
Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer's disease (AD), while how to initiate early cognitive stimulation is unclear. Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing, we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.
After conception, maternal AD transgenic mice (3 × Tg AD) were exposed to gestational environment enrichment (GEE) until the day of delivery. The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age. Western blotting, immunohistochemistry, real-time PCR, immunoprecipitation, chromatin immunoprecipitation (ChIP) assay, electrophysiology, Golgi staining, activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7-10-month-old adult offspring.
We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7-10-m-old AD offspring. The beneficial effects of GEE were accompanied by global histone hyperacetylation, including those at promoter-binding regions, with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus. GEE increased insulin-like growth factor 1 (IGF1) and activated its receptor (IGF1R), which phosphorylates Ca/calmodulin-dependent kinase IV (CaMKIV) at tyrosine sites and triggers its nuclear translocation, subsequently upregulating histone acetyltransferase (HAT) and BDNF transcription. The upregulation of IGF1 mimicked the effects of GEE, while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.
These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.
在痴呆症发病前建立脑储备可能是预防阿尔茨海默病（AD）的一种有前景的策略，然而如何启动早期认知刺激尚不清楚。鉴于未成熟大脑对环境刺激更敏感，且脑动力学随衰老而降低，我们推断早在胎儿期就开始针对AD进行认知刺激可能是有效的。
受孕后，将母本AD转基因小鼠（3×Tg AD）置于孕期环境富集（GEE）条件下直至分娩。当后代在标准环境中饲养至7月龄时，通过莫里斯水迷宫和情境恐惧条件测试评估其认知能力。采用蛋白质免疫印迹法、免疫组织化学法、实时聚合酶链反应、免疫沉淀法、染色质免疫沉淀（ChIP）分析、电生理学、高尔基染色、活性测定和夹心酶联免疫吸附测定法，以深入了解GEE对胚胎和7至10月龄成年后代产生有益作用的潜在机制。
我们发现，GEE显著保留了7至10月龄AD后代的突触可塑性和记忆能力，并改善了标志性病理变化。GEE的有益作用伴随着整体组蛋白高度乙酰化，包括启动子结合区域的组蛋白高度乙酰化，同时胚胎和子代海马体中脑源性神经营养因子（BDNF）的mRNA和蛋白表达增强。GEE增加了胰岛素样生长因子1（IGF1）并激活了其受体（IGF1R），后者在酪氨酸位点使钙/钙调蛋白依赖性激酶IV（CaMKIV）磷酸化并触发其核转位，随后上调组蛋白乙酰转移酶（HAT）和BDNF转录。IGF1的上调模拟了GEE的作用，而孕期抑制IGF1R或HAT则消除了GEE诱导的CaMKIV依赖性组蛋白高度乙酰化和BDNF上调。
这些发现表明，孕期环境富集激活IGF1R/CaMKIV/HAT/BDNF信号通路可能是延缓AD进展的一种有前景的策略。
