In this study, we have applied cell type-specific in vivo biotinylation of proteins (CIBOP) to label Camk2a excitatory neuronal proteomes, and imposed differential centrifugation to prepare synaptosome-enriched fractions, followed by proteomic analysis of biotinylated neuronal proteins. This approach allowed us to obtain the native-state proteome of crude synaptosomes containing presynaptic (mitochondria and synaptic vesicles) and postsynaptic compartments of excitatory neurons from mouse brain, while directly contrasting them with the whole neuronal proteome. Next, we used the systemic LPS-induced neuroinflammation model to activate microglia in an AD-relevant manner, and examined how the synaptic compartment of excitatory neurons responds to neuroinflammatory stress, in contrast with the somatodendritic compartment. We observed that the effects of neuroinflammation on the synaptic compartment were indeed distinct from the somatodendritic compartment, suggestive of compartment-specific effects of neuroinflammation.