Abstract
BackgroundBuilding 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.MethodsAfter 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.ResultsWe 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.ConclusionsThese findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.
Highlights
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
We found that gestational environment enrichment (GEE) increased insulin-like growth factor 1 (IGF1) and activated its receptor (IGF1R), of which the latter directly binds/phosphorylates Ca2+/calmodulin-dependent kinase IV (CaMKIV) to lead to the activation of histone acetyltransferase (HAT) with robust histone acetylation and Brain derived neurotrophic factor (BDNF) production
The offspring were reared in the home cage for 7 m, and learning and memory ability were measured by the Morris water maze (MWM) and contextual fear-conditioning (FC), respectively (Fig. 1a; Additional file 2: Figure S1)
Summary
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. Maternal swimming or treadmill running or voluntary exercise during pregnancy enhances the memory capacity of offspring [8,9,10,11]. These scarce findings of positive effects on offspring are exclusively limited to healthy individuals and have not been extended to disease. We aimed to investigate whether GEE could alter the onset and/or disease severity in transgenic AD models, a devastating disorder that is currently not curable
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