External organic or inorganic objects (foreign bodies) that are inadvertently or purposefully placed in the human or animal tissues can trigger local tissue responses that aim at the elimination and/or segregation of foreign bodies from the tissue. The foreign body response (FBR) may have major implications for neurodegeneration associated with the formation of aberrant protein-based aggregates or plaques. The distinct physical features of the plaques, including high rigidity and varying surface properties, may trigger microglial mechanosensing of the plaque as a foreign body. The microglial FBR may have a dual function by promoting and/or suppressing the plaque driven neurodegeneration. Microglial contact with the plaque may trigger inflammatory activation of microglia and support microglia-driven neuronal damage. Conversely, persistent microglial activation may trigger the formation of a microglia-supported cell barrier that segregates and compacts the plaques thus preventing further plaque-induced damage to healthy neurons.