Thomas Blok

INTRODUCTION Early‐life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid‐beta (Aβ) 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.