NEURITIC PLAQUE EVOLUTION IN ALZHEIMERS-DISEASE IS ACCOMPANIED BY TRANSITION OF ACTIVATED MICROGLIA FROM PRIMED TO ENLARGED TO PHAGOCYTIC FORMS

Activated microglia, overexpressing the potent neuroactive cytokine in terleukin-1, have been implicated as a driving force in the evolution of diffuse amyloid deposits into diagnostic neuritic plaques in Alzhei mer's disease. To evaluate this role further, we used double-label imm unohistochemistry to classify and quantify plaque-associated and non-p laque-associated activated interleukin-1-immunoreactive microglia in p arahippocampal tissue from II patients with Alzheimer's disease. These activated microglia were subclassified as primed (only slightly enlar ged), enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents). We further determined the distribution of these microglial subtypes among four defined plaque types. Most (84%) primed microglia were not plaque associated, although 13% were present in diffuse non- neuritic plaques and 3% were present in diffuse neuritic plaques. Ln c ontrast, most enlarged (55%) and phagocytic (91%) microglia were plaqu e associated. Of plaque-associated enlarged microglia, most (71%) were found in diffuse neuritic plaques with the remainder evenly distribut ed between diffuse non-neuritic and dense-core neuritic plaques (15% e ach). Of plaque-associated phagocytic microglia, a few were present in diffuse non-neuritic plaques (5%), but most were found in diffuse neu ritic plaques (62%) and dense-core neuritic plaques (33%). These findi ngs show preferential association of primed microglia with diffuse amy loid deposits and imply that microglial transformation from primed, to enlarged, to phagocytic types occurs in concert with the evolution of amyloid plaques from diffuse amyloid deposits to the neuritic beta-am yloid plaque forms in Alzheimer's disease. Microglial phagocytic activ ity in neuritic plaques may reflect involvement in the processing of d iffuse amyloid into condensed beta-amyloid, or in clearance of neuriti c debris.