Deteriorative factor and microglial role in Alzheimer's disease

One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. Although the role of microglia in AD pathology has not been clarified, their involvement in Ap clearance has been noted. High mobility group box protein-1 (HMGBl) is an abundant non-histone chromosomal protein. In this study, HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. Diffuse HMGBl immunoreactivity was observed around dying neurons in the kainic acid- and API-42 (AP42)-injected rat hippocampi. HMGBl was also co-localized with AP in the Ap42-injected rats but not in transgenic mice which show massive Ap production without neuronal loss in their brains. Furthermore, co-injection of HMGBl delayed the clearance of Ap42 and accelerated neurodegeneration in Ap42-injected rats. These results suggest that HMGBl released from dying neurons may inhibit microglial AP42 clearance and enhance the neurotoxicity of AP42. Thus, studies of microglia and regulatory factors may provide new insight into the therapeutic strategy for AD.