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.

Synergy between time-restricted feeding and time-restricted running is necessary to shift the muscle clock in male wistar rats.

Circadian disruption is an important factor driving the current-day high prevalence of obesity and type-2 diabetes. While the impact of incorrect timing of caloric intake on circadian disruption is widely acknowlegded, the contribution of incorrect timing of physical activity remains relatively understudied. Here, we modeled the incorrect timing of physical activity in nightshift workers in male Wistar rats, by restricting running wheel access to the innate inactive (light) phase (LR). Controls included no wheel access (NR); access only during the innate active (dark) period (DR); or unrestricted (ad libitum) access (ALR). LR did not shift the phase of the muscle or liver clock, but dampened the muscle clock amplitude. As our previous study demonstrated that light-phase restricted feeding did shift the liver clock, but made the muscle clock arrhythmic, we next combined the time restriction of wheel and food access to either the light phase (LRLF) or dark phase (DRDF). LRLF produced a ∼12 h shift in the majority of clock gene rhythms in both skeletal muscle and liver. On the other hand, DRDF was most effective in reducing body weight and the accumulation of fat mass. Therefore, in order to shift the muscle clock in male Wistar rats, synergy between the timing of feeding and physical activity is necessary. These findings may contribute to further improve the design of lifestyle strategies that try to limit metabolic misalignment caused by circadian disruption.