EARLY LIFE STRESS ACCELERATES AMYLOID PATHOLOGY AND COGNITIVE DECLINE IN APPSWE/PS1DE9 MICE, BUT CAN BE RESCUED BY BRIEFLY BLOCKING GLUCOCORTICOID RECEPTORS AT MIDDLE AGE

Abstract

Exposure to 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 early life stress (ELS) affects AD pathology and cognition in adult and middle-aged APPswe/PS1dE9 mice, and ii) whether it is still possible to later rescue these effects by blocking glucocorticoid receptors (GR) at middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing the dams with limited nesting and bedding material only from postnatal days 2–9 (1,2). At 6 and 12 months of age, different amyloid species, MR/GR, corticosterone and BACE1 levels, and learning and memory performance were determined. The same measures were determined after GRs were blocked at 12 months of age by giving mifepristone for 3 days (3). In 6 and 12 months old offspring, enhanced amyloid-b (Aβ)-40 and -42 levels, enhanced BACE1 levels and cognitive deficits were found, that correlated well with the Aβ42 levels. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced corticosterone levels, reduced hippocampal Ab40/42 and BACE1 levels, and notably, rescued the cognitive deficits in 12 months old APPswe/PS1dE9 mice. This demonstrates that exposure to stress during the sensitive period of early life can modify the emergence of later amyloid pathology, and as such, may increase the vulnerability to AD. The fact that a short treatment with a GR blocker at middle age lastingly reduced Aβ levels and rescued the cognitive deficits after ELS, highlights the therapeutic potential of this drug for reducing amyloid pathology. References 1) Naninck EFG et al., Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus 2015. 2) Lesuis SL et al., Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer's disease. Oncotarget 2016. 3) Krugers HJ et al., Blockade of glucocorticoid receptors rapidly restores hippocampal CA1 synaptic plasticity after exposure to chronic stress. Eur J Neurosci 2006.