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Transl Neurodegener. 2019 Mar 5;8:8. doi: 10.1186/s40035-019-0149-9. eCollection 2019.

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

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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.
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Centre for Disease Control and Prevention, 8 Longyuan Road, Shenzhen, 518055 China.
2Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226000 China.
Contributed equally



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.


Alzheimer’s offspring; Brain-derived neurotrophic factor; Gestational environment enrichment; Histone acetyltransferase; Insulin-like growth factor 1 receptor

Conflict of interest statement

All animal research was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. All efforts were made to minimize the number of animals used and to minimize animal suffering.Not applicable.The authors declare that they have no competing interests.

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