In the brains of Alzheimer's disease (AD) patients, fibrillar amyloid-beta peptides (A beta) are markedly accumulated and the microglia associate with the amyloid plaques, However, the regulation of A P clearance is still unclear. In the present study, we examined the effect of a chaperone protein BiP/GRP78 on the microglial function. Exogenous addition of recombinant BiP/GRP78 induced the production of cytokines such as interleukin-6 and tumor necrosis factor-alpha, but heat treatment of this protein abolished the activity. Although A beta (1-42) did not induce cytokine production, it was taken up by the microglia. In addition, the amount of A beta (1-42) uptake and the number of microglia that phagocytosed A beta (1-42) were markedly increased by BiP/GRP78. Exogenous BiP/GRP78 also translocated to the endoplasmic reticulum (ER). These results suggest that BiP/GRP78 stimulates A beta clearance in the microglia, and that dysfunction in the ER may cause the accumulation of extracellular A beta (1-42).