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 mice. These mouse data demonstrate that exposure to stress during the sensitive period early in life influences later amyloid pathology and cognition in genetically predisposed, mutant mice, and as such, may increase AD vulnerability. The fact that a short treatment with a GR antagonist 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.
Highlights
The mechanisms that underlie sporadic Alzheimer’s disease (AD) remain largely elusive, which hampers the development of successful intervention strategies for AD
For litters born before 10.00 a.m., the day of birth (PND 0) was considered the previous day, after which the early life stress (ELS) paradigm was initiated from postnatal days (PND) 2 to 9
As no Aβ peptides, amyloid precursor protein (APP) or plaques were detected in Ctrl and ELS wild type (WT) mice, these results reveal that ELS lastingly increases hippocampal SDS-soluble Aβ peptide levels in APPswe/PS1dE9 mice, starting from a relatively early age onwards
Summary
The mechanisms that underlie sporadic Alzheimer’s disease (AD) remain largely elusive, which hampers the development of successful intervention strategies for AD. While familial forms of AD can be explained by genetic causes—often related to changes in amyloid-β (Aβ) (e.g. refs 1,2)—sporadic AD likely has a multifactorial aetiology, in which, next to amyloid, lifestyle factors play an important role[2,3,4,5]. Glucocorticoid hormones (GCs; cortisol in humans and corticosterone (CORT) in rodents) are powerful steroids released in response to stress. They are often increased in AD, notably already in early stages of the disease[9,10], and dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is associated with a higher AD risk[8,10,11]
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