Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice

Lan-Yan Lin,Xi-Lin Wu,Yuan-Gui Zhu,Zhen Wei,Wen-Ting Fang,Jing Zhang,Nai-An Xiao,Xiao-Chun Chen,Xiao-Man Dai

doi:10.1186/s13024-016-0107-2

Lan-Yan Lin, Xi-Lin Wu + Show 7 more

Open Access

https://doi.org/10.1186/s13024-016-0107-2

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Abstract

BackgroundApolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice.ResultsAll ApoE-TR mice exposed to CUMS at 3 months old recovered from a depression-like state by the age of 12 months. Of note, ApoE4-TR mice, unlike age-matched ApoE3-TR mice, displayed impaired spatial cognitive abilities, loss of GABAergic neurons, decreased expression of Reelin, PSD95, SYN and Fyn, and reduced phosphorylation of NMDAR2B and CREB.ConclusionThese results suggest that early-life stress may mediate cognitive impairment in middle-age ApoE4-TR mice through sustained reduction of GABAergic neurons and Reelin expression, which might further diminish the activation of the Fyn/NMDAR2B signaling pathway.

Highlights

Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain
chronic unpredictable mild stress (CUMS) procedure successfully induces depression-like behaviors in 3-month-old ApoE-target replacement (TR) mice To assess the impact of the CUMS procedure, we evaluated the weight, sucrose consumption and behavior of ApoE3/4-TR mice undergoing CUMS compared to controls
While the weights of mice in the control groups steadily increased during weeks 12–18, the weights of mice undergoing CUMS leveled off, with a significant difference between the control groups and the ApoE4TR mice observed in the fifth week (Fig. 2a)

Summary

Introduction

Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice. Recent studies have reported that early-life symptoms of depression can increase the risk of cognitive impairment in old age [8,9,10], and that adverse events in childhood have a more severe effect on the depressive symptoms present in older-age ApoE4 carriers, as compared to ApoE4 non-carriers [11].

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