Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain

Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models and human AD postmortem brains. We identified commonly changed phosphoproteins in multiple models and also determined phosphoproteins related to initiation of Abeta deposition in the mouse brain. We put the proteins on experimentally verified protein-protein interaction databases. Surprisingly most of the core phosphoproteins were directly connected, and they formed a functional network linked to synaptic spine formation. The change of the core network started at a preclinical stage even before histological Abeta deposition. Systems biology analyses suggested phosphorylation of MARCKS by over-activated kinases including PKCs and CaMKs initiates synapse pathology.