Proteomic analysis of postsynaptic density in Alzheimer's Disease

• Report a pilot proteomic analysis of synaptic proteins from Alzheimer's Disease
• Demonstrate the feasibility of isolating postsynaptic density from AD brain
• Analyze clinical samples in biological replicates by two proteomic methods
• Validate selected proteins (internexin and IRSp53) by immunoblotting

BackgroundThe loss of synaptic function is a pivotal mechanism in the development of Alzheimer's Disease (AD). Structural changes and loss of plasticity in the postsynaptic density (PSD) may contribute to the pathogenesis. However, the underlying molecular events triggering synaptic dysfunction remain elusive. We report a quantitative proteomic analysis of the PSD from human postmortem brain tissues of possible and definite AD cases.MethodsThe analysis used both discovery and targeted mass spectrometry approaches and was repeated with biological replicates. During the discovery study, we compared several hundred proteins in the PSD-enriched fractions and found that 25 proteins were differentially regulated in AD.ResultsInterestingly, the majority of these protein changes were larger in definite AD cases than in possible AD cases. In the targeted analysis, we measured the level of 9 core PSD proteins and found that only IRSp53 was highly down-regulated in AD. The alteration of selected proteins (i.e. internexin and IRSp53) was further validated by immunoblotting against 7 control and 8 AD cases.ConclusionsThese results expand our understanding of how AD impacts PSD composition, and hints at new hypotheses for AD pathogenesis.