Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins.
Alzheimer's disease (AD) is characterized by the accumulation of fibrillar amyloid-beta (Abeta) peptides to form amyloid plaques. Understanding the balance of production and clearance of Abeta peptides is the key to elucidating amyloid plaque homeostasis. Microglia in the brain, associated with senile plaques, are likely to play a major role in maintaining this balance. Here, we show that heat-shock proteins (HSPs), such as HSP90, HSP70, and HSP32, induce the production of interleukin 6 and tumor necrosis factor alpha and increase the phagocytosis and clearance of Abeta peptides. This suggests that microglial interaction with Abeta peptides is highly regulated by HSPs. The mechanism of microglial activation 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 Abeta clearance and cytokine production
Kakimura
Jun-Ichi
J
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan. .
Kitamura
Yoshihisa
Y
Takata
Kazuyuki
K
Umeki
Masaaki
M
Suzuki
Sanae
S
Shibagaki
Keiichi
K
Taniguchi
Takashi
T
Nomura
Yasuyuki
Y
Gebicke-Haerter
Peter J
PJ
Smith
Mark A
MA
Perry
George
G
Shimohama
Shun
S
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000494:pharmacology; D051547:Heme Oxygenase-1; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010587:Phagocytosis; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D016229:Amyloid beta-Peptides; D016207:Cytokines; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C075222:amyloid beta-protein (1-42); C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse