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

Abstract

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

Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus

“…A slight repression (1.7-fold) of hsp86 transcription could be detected in the hippocampus of the fish oil-fed animals. In AD brains, levels of heat shock proteins were increased in both the cytosolic and membranous fractions, and chaperonine HSP90 was colocalized with amyloid plaques (50). However, there might be some correlation between the altered expression of these genes and neurological functions; the magnitude of these changes are not significant.…”

Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression

“…Although the signals that activate microglia in vivo are defined incompletely, several studies using in vitro models have shown that microglia respond to cytokines (IL-1 , TNF-and IFN-), microbial products, such as bacterial LPS, and certain diseaserelated abnormal proteins, including -amyloid, human immunodeficiency virus (HIV)-specific gp41 and HIV-Tat, prions (Nakamura et al, 2002), and heat shock proteins (Kakimura et al, 2002). These factors activate their receptors and activate intracellular signaling pathway.…”

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

“…59 In AD brains, levels of HSP90 are increased in both the cytosolic and membranous fractions, where HSP90 is thought to maintain tau and Ab in a soluble conformation, thereby averting their aggregation. 93,94 Martínez-Ruiz et al 92 recently demonstrated that S-nitrosylation of HSP90 can occur in endothelial cells, and this modification abolishes its ATPase activity, which is required for its function as a molecular chaperone. These studies suggest that S-nitrosylation of HSP90 in neurons of AD brains may possibly contribute to the accumulation of tau and Ab aggregates.…”