Early-life stress induces the development of Alzheimer's disease pathology via angiopathy

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a major societal, scientific, and economic problem. Several early-life factors associated with an increased risk for the clinical diagnosis of AD have recently been identified. In the present study, we investigated the involvement of early-life stress in the pathogenesis of AD using heterozygous amyloid precursor protein (APP) mutant mice (App(NL-G-F/wt)) and wild-type (App(wt/wt)) mice. We found that maternal-separated App(wt/wt) mice showed narrowing of vessels and decreased pericyte coverage of capillaries in the prefrontal cortex, while maternal-separated App(NL-G-F/wt) mice additionally showed the impairment of cognitive function, earlier formation of A beta plaques, increased vessel-associated microglia, and disruption of the blood-brain barrier. Substantial activation of microglia was detected in the maternal-separated App(NL-G-F/wt) mice and maternal-separated App(wt/wt) mice. At an early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separated App(NL-G-F/wt) mice and maternal-separated App(wt/wt) mice, and morphological changes in the microglia were observed in the non-maternal-separated App(NL-G-F/wt )mice. Microglia activation induced by maternal separation in combination with the APP mutation may impair the vascular system, leading to AD progression. These findings therefore suggest that maternal separation results in the early induction of AD-related pathology via angiopathy.