Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism.

INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aß) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear. METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence. RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins. DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions.

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2-9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

Sex-dependence and comorbidities of the early-life adversity induced mental and metabolic disease risks: Where are we at?

Early-life adversity (ELA) is a major risk factor for developing later-life mental and metabolic disorders. However, if and to what extent ELA contributes to the comorbidity and sex-dependent prevalence/presentation of these disorders remains unclear. We here comprehensively review and integrate human and rodent ELA (pre- and postnatal) studies examining mental or metabolic health in both sexes and discuss the role of the placenta and maternal milk, key in transferring maternal effects to the offspring. We conclude that ELA impacts mental and metabolic health with sex-specific presentations that depend on timing of exposure, and that human and rodent studies largely converge in their findings. ELA is more often reported to impact cognitive and externalizing domains in males, internalizing behaviors in both sexes and concerning the metabolic dimension, adiposity in females and insulin sensitivity in males. Thus, ELA seems to be involved in the origin of the comorbidity and sex-specific prevalence/presentation of some of the most common disorders in our society. Therefore, ELA-induced disease states deserve specific preventive and intervention strategies.

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

Early-life stress (ES) increases the risk for psychopathology and cognitive decline later in life. Because the neurobiological substrates affected by ES (i.e., cognition, neuroplasticity, and neuroinflammation) are also altered in aging, we set out to investigate if and how ES in the first week of life affects these domains at an advanced age, and how ES modulates the aging trajectory per se. We subjected C57BL/6j mice to an established ES mouse model from postnatal days 2-9. Mice underwent behavioral testing at 19 months of age and were sacrificed at 20 months to investigate their physiology, hippocampal neuroplasticity, neuroinflammation, and telomere length. ES mice, as a group, did not perform differently from controls in the open field or Morris water maze (MWM). Hippocampal neurogenesis and synaptic marker gene expression were not different in ES mice at this age. While we find aging-associated alterations to neuroinflammatory gene expression and telomere length, these were unaffected by ES. When integrating the current data with those from our previously reported 4- and 10-month-old cohorts, we conclude that ES leads to a 'premature' shift in the aging trajectory, consisting of early changes that do not further worsen at the advanced age of 20 months. This could be explained e.g. by a 'floor' effect in ES-induced impairments, and/or age-induced impairments in control mice. Future studies should help understand how exactly ES affects the overall aging trajectory.

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

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-ß pathology.