Abstract
Life-time experiences are thought to influence the risk to develop the neurodegenerative disorder Alzheimer’s disease (AD). In particular, early-life stress (ES) may modulate the onset and progression of AD. There is recent evidence by our group and others that AD-related neuropathological progression and the associated neuroimmune responses are modulated by ES in the classic APPswe/PS1dE9 mouse model for AD. We here extend our previous study on ES mediated modulation of neuropathology and neuroinflammation and address in the same cohort of mice whether ES accelerates and/or aggravates AD-induced cognitive decline and alterations in the process of adult hippocampal neurogenesis (AHN), a form of brain plasticity. Chronic ES was induced by limiting bedding and nesting material during the first postnatal week and is known to induce cognitive deficits by 4 months in wild type (WT) mice. The onset of cognitive decline in APP/PS1 mice generally starts around 6 months of age. We here tested mice at ages 2–4 months to study acceleration and at ages 8–10 months for aggravation of the APP/PS1 phenotype. ES-exposed WT and APP/PS1 mice were able to perform the object recognition (ORT) and location tasks (OLT) at 2 months of age. Interestingly, at 3 months, ES induced impairments in the performance of the OLT in WT, but not in APP/PS1 mice. APP/PS1 mice exhibited alterations in hippocampal cell proliferation and differentiation, but ES exposure did not further change this. At 9 months, APP/PS1 mice exhibited impaired performance in the Morris Water Maze (MWM) task, as well as reductions in markers of the AHN process, which were not further modulated by ES exposure. In addition, we observed a so far unreported hyperactivity in ES-exposed mice at 8 months of age, which hampered assessment of cognitive functions in the ORT and OLT. In conclusion, while ES has been reported to modulate AD neuropathology and neuroinflammation before, it failed to accelerate or aggravate the decline in cognition or the process of AHN in APP/PS1 mice at ages 2–4 and 8–10 months. Future studies are needed to unravel how ES might affect the vulnerability to develop AD.
Highlights
Alzheimer’s disease (AD) is the most prevalent form of dementia in elderly
Spatial Memory Is Impaired by early-life stress (ES) at 3 Months of Age in wild type (WT) Mice, But Not in amyloid precursor protein (APP)/PS1 Mice With or Without ES Exposure A second cohort was tested for cognitive performance in the object location task (OLT) at the age of 3 months (Figure 1F)
At 4 months of age, the APP/PS1 mice further exhibited an increased number of differentiating DCX expressing cells, but a decrease in BrdU+ cell numbers in the sub granular zone (SGZ). These indicators of the neurogenic process did not correlate with OLT performance of these mice at 3 months, whereas BrdU+ cell numbers were associated with the APP/PS1-induced neuropathological and microglial changes at 4 months, that we reported before Hoeijmakers et al (2017)
Summary
Alzheimer’s disease (AD) is the most prevalent form of dementia in elderly. It is characterized by an age-related accumulation of amyloid β (Aβ) neuropathology and tau-related neurofibrillary tangles in the brain (Querfurth and LaFerla, 2010; Scheltens et al, 2016). Recent clinical studies have further suggested that exposure to stress or trauma early in life might enhance the vulnerability to develop dementia later in life (Seifan et al, 2015; Wang et al, 2016), the study of this hypothesis has only recently begun. Early-life stress (ES) has been shown to induce deficits in adult hippocampal structure and functioning, as well as cognitive impairments in both humans and rodent ES models (Staff et al, 2012; Naninck et al, 2015; Wang et al, 2016; Calem et al, 2017)
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