Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.27.062729v1?rss=1 Authors: Tanaka, T., Hirai, S., Hosokawa, M., Saito, T., Sakuma, H., Saido, T., Hasegawa, M., Okado, H. Abstract: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a serious social problem. Recently, several early-life factors have been associated with an increased risk of a clinical diagnosis of AD. In the present study, we investigated the involvement of early-life stress in AD pathogenesis using heterozygous APP mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. Maternal separation was used as an animal paradigm for early-life stress. We found that stressed Appwt/wt mice showed narrowing of vessels and decreased pericyte coverage of capillaries in prefrontal cortex, while stressed AppNL-G-F/wt mice showed impairment of place memory, and earlier formation of A{beta} plaques and disruption of the blood-brain barrier than non-stressed AppNL-G-F/wt mice. We detected severe activation of microglia in the stressed AppNL-G-F/wt mice and stressed Appwt/wt mice. In the earlier stage, we detected morphological change and functional change in microglia in the stressed AppNL-G-F/wt mice and stressed Appwt/wt mice, and also detected morphological change in the microglia in the non-stressed AppNL-G-F/wt mice. Therefore, we hypothesize that activated microglia induced by the combination of maternal separation and APP mutation impairs the vascular system, leading to AD progression. These findings therefore suggest that maternal separation causes early induction of AD pathology. Copy rights belong to original authors. Visit the link for more info