The formation of misfolded protein oligomers during early stages of amyloid aggregation and the activation of neuroinflammatory responses are two key events associated with neurodegenerative diseases. Although it has been established that misfolded oligomers are involved in the neuroinflammatory process， the links between their structural features and their functional effects on the immune response remain unknown. To explore such links， we took advantage of two structurally distinct soluble oligomers (type A and B) of protein HypF-N and compared the elicited microglial inflammatory responses. By using confocal microscopy， protein pull-down， and high-throughput mass spectrometry， we found that， even though both types bound to a common pool of microglial proteins， type B oligomers-with a lower solvent-exposed hydrophobicity-showed enhanced protein binding， correlating with the observed inflammatory response. Furthermore， the interactome associated with inflammatory-mediated neurodegeneration revealed previously unidentified receptors and signaling molecules likely to be involved in the oligomer-elicited innate immune response.