|Budget Amount *help
¥16,500,000 (Direct Cost: ¥16,500,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥10,500,000 (Direct Cost: ¥10,500,000)
Exogenous addition of recombinant Bip/GRP78 induced the production of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but heat treatment of this protein abolished the activity. Although Aβ (1-42) did not induce cytokine production, it was taken up by the microglia. In addition, the amount of Aβ (1-42) uptake and the number of microglia that phagocytosed Aβ (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 Aβ clearance in the microglia, and that dysfunction in the ER may cause the accumulation of extracellular Aβ (1-42). Heat-shock proteins (HSPs), such as HSP90, HSP70, and HSP32, induce the production of IL-6 and TNF-α and increase the phagocytosis and clearance of Aβ peptides, suggesting that microglial interaction with Aβ peptides is highly regulated by HSPs. The mechanism of microglial interaction by exogenous HSPs involves the nuclear factor kB and p38 mitogen-activated protein kinase pathways mediated by Toll-like receptor 4 activation. In AD brains, levels of HSP90 were increased in both the cytosolic and membranous fractions, and HSP90 was colocalized with amyloid plaques. These observations suggest that HSP-induced microglial activation may serve a neuroprotective role by facilitating Aβ clearance and cytokine production. High mobility group protein-1 (HMG1) inhibited the microglial uptake of Aβ (1-42) in the presence and absence of transforming growth factor-β1 (TGF-β1). In addition, HMG1 bound to Aβ (1-42) and stabilized the oligomerization. In AD brains, protein levels of HMG1 were significantly increased in both the cytosolic and particulate fractions, and HMG1 and Aβ were colocalized in senile plaques associated with microglia. These results suggest that HMG1 may regulate the homeostasis of extracellular Aβ (1-42) and Aβ oligomerization.