Bip/GRP78-induced production of cytokines and uptake of amyloid-beta(1-42) peptide in microglia.
In the brains of Alzheimer's disease (AD) patients, fibrillar amyloid-beta peptides (Abeta) are markedly accumulated and the microglia associate with the amyloid plaques. However, the regulation of Abeta 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 Abeta(1-42) did not induce cytokine production, it was taken up by the microglia. In addition, the amount of Abeta(1-42) uptake and the number of microglia that phagocytosed Abeta(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 Abeta clearance in the microglia, and that dysfunction in the ER may cause the accumulation of extracellular Abeta(1-42).
Kakimura
J
J
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, 607-8412, Japan.
Kitamura
Y
Y
Taniguchi
T
T
Shimohama
S
S
Gebicke-Haerter
P J
PJ
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007700:Kinetics; D017628:Microglia / Q000378:metabolism*; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000378:metabolism*; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000737:chemistry*; D010587:Phagocytosis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)