Extracellular Hsp90α Detoxifies β-Amyloid Fibrils Through an NRF2 and Autophagy Dependent Pathway

We have investigated the role of e xtracellular H eat s hock p rotein 90 alpha (eHsp90α) in conferring protection of neuronal cells against fibrillary amyloid beta (f-Aβ 1-42 ) toxicity mediated by microglial cells. Formation of f-Aβ 1-42 plaques leads to neurotoxic inflammation, a critical pathological feature of Alzheimer’s Disease. We observed increased uptake and clearance of internalized f-Aβ 1-42 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-Aβ 1-42 -activated microglia. In addition, eHsp90α facilitated f-Aβ 1-42 engulfment by microglial cells in vitro . In summary, eHsp90α triggers NRF2-mediated autophagy in microglia and thus protects against the neurotoxic effects of f-Aβ 1-42 .