Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

Abstract

Background: Early-life stress (ES) is an emerging risk factor for later life development of Alzheimer's disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice and how these relate to the previously reported amyloid pathology and microglial profile. Methods: We induced ES by limiting nesting and bedding material from postnatal days (P) 2-9. We studied in WT mice (at P9, P30, and 6 months) and in APP/PS1 mice (at 4 and 10 months) (i) GFAP coverage, cell density, and complexity in hippocampus (HPC) and entorhinal cortex (EC); (ii) hippocampal gene expression of astrocyte markers; and (iii) the relationship between astrocyte, microglia, and amyloid markers.Results: In WT mice, ES increased GFAP coverage in HPC subregions at P9 and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age.Conclusions: Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.

Early-life stress does not alter spatial memory performance, hippocampal neurogenesis, neuroinflammation, or telomere length in 20-month-old male mice

“…Of course, these data do not preclude the possibility that ES might have modulatory effects at in-between as well as at later time-points, or how ES might interact with secondary “hits” that could alter the aging process. We and others have described how ES phenotypes are affected by challenges such as acute stress ( Bonapersona et al, 2019 ), diet ( Abbink et al, 2020b ; Ruigrok et al, 2021 ; Yam et al, 2017 ), and amyloid-β neuropathology ( Abbink et al, 2020a ; Hoeijmakers et al, 2017 , 2018a ), and it remains to be seen how these second hits might further alter the aging trajectory in the context of ES.…”

Early life adversity as a risk factor for cognitive impairment and Alzheimer’s disease

“…The potential involvement of ELA in AD has been studied in rodent models (Table 3 ). APPswe/PS1dE9 mice exposed to LBN displayed aggravated Aβ plaque load at 10 months of age accompanied by increased glial activation and inflammatory signals in the hippocampus [ 76 , 77 ]. LBN also increased the hippocampal levels of Aβ40 and Aβ42 and elevated the level of β-site APP-cleaving enzyme 1 (BACE1), a key rate-limiting enzyme for Aβ processing and production, in this mouse model [ 78 ].…”

Age-Dependent Hippocampal Proteomics in the APP/PS1 Alzheimer Mouse Model: A Comparative Analysis with Classical SWATH/DIA and directDIA Approaches

“…For example, APP/PS1 mice show early elevated Aβ production and plaque formation in the hippocampus observed at 6 months of age (moa), which increases progressively with age [6]. In addition, these mice show synaptic dysfunction [7,8], presence of reactive astrocytes [9] and microglia [10], and multiple forms of memory impairments [8,11]. Studies have indicated synapse loss as early events in AD, which especially affect the hippocampus, and correlates with cognitive decline [3,12].…”