The Toxin BDS-I Protects Astrocytes Exposed to Aβ Oligomers by Restoring [Ca] Transients and ER Ca Signaling.

Intracellular calcium concentration ([Ca]) transients in astrocytes represent a highly plastic signaling pathway underlying the communication between neurons and glial cells. However, how this important phenomenon may be compromised in Alzheimer's disease (AD) remains unexplored. Moreover, the involvement of several K channels, including K3.4 underlying the fast-inactivating currents, has been demonstrated in several AD models. Here, the effect of K3.4 modulation by the marine toxin blood depressing substance-I (BDS-I) extracted from has been studied on [Ca] transients in rat primary cortical astrocytes exposed to Aβ oligomers. We showed that: (1) primary cortical astrocytes expressing K3.4 channels displayed [Ca] transients depending on the occurrence of membrane potential spikes, (2) BDS-I restored, in a dose-dependent way, [Ca] transients in astrocytes exposed to Aβ oligomers (5 µM/48 h) by inhibiting hyperfunctional K3.4 channels, (3) BDS-I counteracted Ca overload into the endoplasmic reticulum (ER) induced by Aβ oligomers, (4) BDS-I prevented the expression of the ER stress markers including active caspase 12 and GRP78/BiP in astrocytes treated with Aβ oligomers, and (5) BDS-I prevented Aβ-induced reactive oxygen species (ROS) production and cell suffering measured as mitochondrial activity and lactate dehydrogenase (LDH) release. Collectively, we proposed that the marine toxin BDS-I, by inhibiting the hyperfunctional K3.4 channels and restoring [Ca] oscillation frequency, prevented Aβ-induced ER stress and cell suffering in astrocytes.