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Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease
Translational Neurodegeneration ( IF 12.6 ) Pub Date : 2019-03-05 , DOI: 10.1186/s40035-019-0149-9
Enjie Liu 1, 2 , Qiuzhi Zhou 1 , Ao-Ji Xie 1 , Mengzhu Li 1 , Shujuan Zhang 1 , Hezhou Huang 1 , Zhenyu Liuyang 1 , Yali Wang 1 , Bingjin Liu 1 , Xiaoguang Li 1 , Dongsheng Sun 1 , Yuping Wei 1 , Xiaochuan Wang 1 , Qun Wang 1 , Dan Ke 1 , Xifei Yang 3 , Ying Yang 1 , Jian-Zhi Wang 1, 4
Affiliation  

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 bdnf 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 Ca2+/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.

中文翻译:

丰富的妊娠激活 IGF 通路以唤起胚胎-成人的益处以预防阿尔茨海默病

在痴呆症发作之前建立大脑储备可能是预防阿尔茨海默病 (AD) 的一种有前途的策略,而如何启动早期认知刺激尚不清楚。鉴于未成熟的大脑对环境刺激更敏感,并且大脑动态随着年龄的增长而下降,我们推断早在胎儿时期就开始对 AD 进行认知刺激是有效的。受孕后,母体 AD 转基因小鼠 (3 × Tg AD) 被暴露于妊娠环境富集 (GEE) 直到分娩当天。当后代在标准环境中长大至 7 个月大时,通过莫里斯水迷宫和情境恐惧条件测试评估后代的认知能力。Western印迹,免疫组织化学,实时PCR,免疫沉淀,染色质免疫沉淀 (ChIP) 测定、电生理学、高尔基染色、活性测定和夹心 ELISA 用于深入了解 GEE 对胚胎和 7-10 个月大的成年后代的有益影响的机制。我们发现 GEE 显着保留了突触可塑性和记忆能力,并改善了 7-10 岁 AD 后代的标志性病变。GEE 的有益作用伴随着全局组蛋白高乙酰化,包括那些在 bdnf 启动子结合区域的组蛋白,在胚胎和后代海马中都有强大的 BDNF mRNA 和蛋白质表达。GEE 增加胰岛素样生长因子 1 (IGF1) 并激活其受体 (IGF1R),该受体在酪氨酸位点磷酸化 Ca2+/钙调蛋白依赖性激酶 IV (CaMKIV) 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,而怀孕期间的 IGF1R 或 HAT 抑制消除了 GEE 诱导的 CaMKIV 依赖性组蛋白高乙酰化和 BDNF 上调。这些发现表明,通过妊娠环境富集激活 IGF1R/CaMKIV/HAT/BDNF 信号可能是一种有前途的延缓 AD 进展的策略。
更新日期:2020-04-22
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