Association of microglia with amyloid plaques in brains of APP23 transgenic mice

Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although t here is evidence that microglial activation is important for the pathogenes is of AD, the role of microglia in cerebral amyloidosis remains obscure. Th e present study was undertaken to investigate the relationship between beta -amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (PPP) under the contr ol of a neuron-specific promoter element. Light microscopic analysis reveal ed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with cluste rs of hypertrophic microglia with intensely stained Mac-1- and phosphotyros ine-positive processes. No association of such activated microglia was obse rved with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surround ed by an incomplete membrane, were observed within the microglial cytoplasm , However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibri ls, Although the present observations cannot unequivocally determine whethe r microglia are causal, contributory, or consequential to cerebral amyloido sis, our results suggest that microglia are involved in cerebral amyloidosi s either by participating in the processing of neuron-derived PPP into amyl oid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytoti c mechanism. In any case, our observations demonstrate that neuron-derived PPP is sufficient to induce not only amyloid plaque formation but also amyl oid-associated microglial activation similar to that reported in AD. Moreov er, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.