Progesterone exerts neuroprotective effects against Aβ-induced neuroinflammation by attenuating ER stress in astrocytes

• ER stress activation is involved in Aβ-induced neuroinflammation in astrocytes.
• PG exerts neuroprotection against Aβ-induced neuroinflammation in astrocytes.
• PG suppresses Aβ-induced ER stress activation in astrocytes.

The deposition of amyloid-β (Aβ) and neuroinflammation are critical pathological features of Alzheimer's disease (AD). Astrocytes are considered the principal immunoregulatory cells in the brain. Neurosteroid progesterone (PG) exerts neuromodulatory properties, particularly its potential therapeutic function in ameliorating AD. However, the role of PG and the neuroprotective mechanism involving in the regulation of neuroinflammation in astrocytes warrant further investigation. In this study, we found that Aβ significantly increased the processing of neuroinflammatory responses in astrocytes. The processing is induced by an increase activity of PERK/elF2ɑ-dependent endoplasmic reticulum (ER) stress. Additionally, the inhibition of ER stress activation by Salubrinal significantly suppressed the Aβ-induced neuroinflammatory responses in astrocytes. While the treatment of astrocytes with Aβ caused an increase of neuroinflammatory responses, PG significantly inhibited Aβ-induced neuroinflammatory cytokine production by suppressing ER stress activation together with attenuating PERK/elF2ɑ signalling. Taken together, these results indicate that PG exerts a neuroprotective effect against Aβ-induced neuroinflammatory responses, and significantly suppresses ER stress activation, which is an important mediator of the neurotoxic events occurring in Aβ-induced neuroinflammatory responses in astrocytes. These neuroprotective mechanisms may facilitate the development of therapies to ameliorate AD.