Age-dependent impact of early-life stress on glia and synapses Substrates for increased risk for Alzheimer’s disease

Exposure to early-life stress (ES) is associated with later-life health outcomes, such as Alzheimer’s disease (AD). While the mechanisms behind such lasting vulnerabilities are unknown, one hypothesis is that ES impacts how individuals age, in part by altering their response to later-life challenges.
This thesis tested these ideas, using both wildtype and AD-transgenic mouse models that were aged after ES treatment. Our work focused on the hippocampus, and aimed to: 1) study the ES phenotype at advanced-aged rodents; 2) characterize how microglia from ES-exposed mice, which are the innate immune cells in the brain, are altered in basal and immune challenged states; 3) characterize how ES impacts hippocampal synaptic protein expression in both wildtype and AD-transgenic mice; and 4) explore how astrocytes, a major cell type around synapses, are impacted by ES treatment.
Our work suggests a lasting impact of ES on the studied neurobiological substrates, particularly in microglia. Microglia from ES mice exhibit altered transcriptional profiles both at baseline and after immune activation, and phagocytose synapses differently. We also found alterations to protein composition both in synapses and the astrocytes around them, especially in ES-exposed AD-transgenic mice, which can also be seen as an immune challenge.
While we did not find strong effects of ES exposure in unperturbed, aged mice, our data support the notion that these effects are occur latently, and can be ‘unmasked’ with secondary ‘hits.’ A better understanding of these mechanisms can hopefully be used to eventually help individuals with such experiences cope and flourish.