High mobility group box protein‐1 inhibits microglial Aβ clearance and enhances Aβ neurotoxicity

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Abstract
One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. According to the amyloid hypothesis, the increase or accumulation of amyloid‐β (Aβ) peptides in the brain parenchyma is the primary event that influences AD pathology. Although the role of microglia in AD pathology has not been clarified, their involvement in Aβ clearance has been noted. High mobility group box protein‐1 (HMGB1) is an abundant nonhistone chromosomal protein. We reported recently that HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. In this study, diffuse HMGB1 immunoreactivity was observed around dying neurons in the kainic acid‐ and Aβ1–42 (Aβ42)‐injected rat hippocampi. HMGB1 also colocalized with Aβ in the Aβ42‐injected rats but not in transgenic mice, which show massive Aβ production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Aβ42 and accelerated neurodegeneration in Aβ42‐injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Aβ42 clearance and enhance the neurotoxicity of Aβ42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD.