Microglial activation and amyloid‐β clearance induced by exogenous heat‐shock proteins

• Published in: The FASEB journal 2002-04, Vol.16 (6), p.601-603
• Main Authors: Kakimura, Jun-Ichi, Kitamura, Yoshihisa, Takata, Kazuyuki, Umeki, Masaaki, Suzuki, Sanae, Shibagaki, Keiichi, Taniguchi, Takashi, Nomura, Yasuyuki, Gebicke-Haerter, Peter J., Smith, Mark A., Perry, George, Shimohama, Shun
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Cells, Cultured; cytokines; Cytokines - biosynthesis; Drosophila Proteins; Heat-Shock Proteins - pharmacology; Heme Oxygenase (Decyclizing) - pharmacology; Heme Oxygenase-1; HSP70 Heat-Shock Proteins - pharmacology; HSP90 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - pharmacology; Humans; Kinetics; Membrane Glycoproteins - metabolism; Membrane Proteins; Mice; microglia; Microglia - drug effects; Microglia - physiology; Models, Biological; neuroprotection; Neuroprotective Agents - pharmacology; Peptide Fragments - metabolism; Phagocytosis; Rats; Receptors, Cell Surface - metabolism; Toll-Like Receptor 4; Toll-Like Receptors
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.01-0530fje

ABSTRACT Alzheimer's disease (AD) is characterized by the accumulation of fibrillar amyloid‐β (Aβ) peptides to form amyloid plaques. Understanding the balance of production and clearance of Aβ 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 α and increase the phagocytosis and clearance of Aβ peptides. This suggests that microglial interaction with Aβ 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 Aβ clearance and cytokine production.