Updated project metadata. The deposition of amyloid senile plaques (SPs) plays a central role in Alzheimer’s disease (AD), but the mechanisms by which SPs induce neural toxicity are disputed. Genetically engineered mouse models emphasizing SPs have had limited success in reproducing the neuropathology of AD, and have also failed to be good indicators of successful amyloid-targeting therapies. Therefore, it is fundamentally important to fully characterize and distinguish the pathological changes elicited by SPs in human and mouse brains. Using laser capture microdissection (LCM) combined with high-throughput mass spectrometry, we quantified ~5000 proteins with high confidence in SPs and non-plaque regions from APP/PS1 mouse model brain. We found more proteomic alteration in SPs than in non-plaque regions, and identified more than 200 mouse proteins that were significantly enriched in SPs. Together, our findings represent the most systematic analysis of the sub-proteome of SPs and provide a framework for future studies on plaque pathology and AD progression.