Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease

查看全文 作　　者：Enjie [1,4]Liu;Qiuzhi [1]Zhou;Ao-Ji [1]Xie;Mengzhu [1]Li;Shujuan [1]Zhang;Hezhou [1]Huang;Zhenyu [1]Liuyang;Yali [1]Wang;Bingjin [1]Liu;Xiaoguang [1]Li;Dongsheng [1]Sun;Yuping [1]Wei;Xiaochuan [1]Wang;Qun [1]Wang;Dan [1]Ke;Xifei [3]Yang;Ying [1]Yang;Jian-Zhi [1,2]Wang

机构地区：[1]Department 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;[2]Co-innovation Center of Neuroregeneration,Nantong University,Nantong 226000,China;[3]Key Laboratory of Modern Toxicology of Shenzhen,Shenzhen Centre for Disease Control and Prevention,8 Longyuan Road,Shenzhen 518055,China;[4]Department of Pathology,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China

出　　处：《Translational Neurodegeneration》索引2019年第8卷第1期,共17页

基　　金：This work was supported in part by grants from the NSFC(91632305,91632111,31730035 and 81721005);by the Ministry of Science and Technology of China(2016YFC1305800). 摘　　要：Background: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.Methods: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.Results: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 Ca^(2+)/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.Conclusions: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. 关键词：Alzheimer’s offspring Brain-derived neurotrophic factor Gestational environment enrichment Histone acetyltransferase Insulin-like growth factor 1 receptor

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Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease

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