We have investigated the role of extracellular Heat shock protein 90 alpha (eHsp90α) in conferring protection of neuronal cells against fibrillary amyloid-beta (f-Aβ1-42) toxicity mediated by microglial cells. The formation of f-Aβ1-42 plaques leads to neurotoxic inflammation, a critical pathological feature of Alzheimer's Disease. We observed increased uptake and clearance of internalized f-Aβ1-42 by microglial cells treated with eHsp90α, an effect associated with activation of NRF2 (NF-E2-related factor 2) - mediated autophagy. eHsp90α thus mitigated the neuronal toxicity of f-Aβ1-42-activated microglia. In addition, eHsp90α facilitated f-Aβ1-42 engulfment by microglial cells in vitro. In summary, eHsp90α triggers NRF2-mediated autophagy in microglia and thus protects against the neurotoxic effects of f-Aβ1-42.
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