Targeting glucocorticoid receptors prevents the effects of early life stress on amyloid pathology and cognitive performance in APP/PS1 mice

Translational Psychiatry
Sylvie L LesuisHarm J Krugers

Abstract

Exposure to chronic stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer's disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; (i) whether chronic early life stress (ELS) affects AD pathology and cognition in middle-aged APPswe/PS1dE9 mice, and (ii) whether it is still possible to rescue these late effects by briefly blocking glucocorticoid receptors (GRs) at a translationally relevant, middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing dams and pups with limited nesting and bedding material from postnatal days 2-9 only. In 6- and 12-month-old offspring, this resulted in enhanced hippocampal amyloid-β (Aβ)-40 and -42 levels, and in reduced cognitive flexibility, that correlated well with the Aβ42 levels. In parallel, CORT levels and BACE1 levels were significantly elevated. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced CORT levels, reduced hippocampal Aβ40 and -42, and β-site APP-cleaving enzyme 1 (BACE1) levels, and notably rescued the cognitive deficits in 12-month-old APPswe/PS1dE9 mic...Continue Reading

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Citations

Mar 22, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Katharina DietrichThomas A Bayer
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Nov 4, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Sik Yu So, Tor C Savidge

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Methods Mentioned

BETA
genotyping
Protein Assay
enzyme-linked immunosorbent assay
transgenic

Software Mentioned

ImageJ

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