The Anemonia sulcata Toxin BDS-I Protects Astrocytes Exposed to Aβ(1–42) Oligomers by Restoring [Ca(2+)](i) Transients and ER Ca(2+) Signaling

Intracellular calcium concentration ([Ca(2+)](i)) 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 K(V)3.4 underlying the fast-inactivating currents, has been demonstrated in several AD models. Here, the effect of K(V)3.4 modulation by the marine toxin blood depressing substance-I (BDS-I) extracted from Anemonia sulcata has been studied on [Ca(2+)](i) transients in rat primary cortical astrocytes exposed to Aβ(1–42) oligomers. We showed that: (1) primary cortical astrocytes expressing K(V)3.4 channels displayed [Ca(2+)](i) transients depending on the occurrence of membrane potential spikes, (2) BDS-I restored, in a dose-dependent way, [Ca(2+)](i) transients in astrocytes exposed to Aβ(1–42) oligomers (5 µM/48 h) by inhibiting hyperfunctional K(V)3.4 channels, (3) BDS-I counteracted Ca(2+) overload into the endoplasmic reticulum (ER) induced by Aβ(1–42) oligomers, (4) BDS-I prevented the expression of the ER stress markers including active caspase 12 and GRP78/BiP in astrocytes treated with Aβ(1–42) oligomers, and (5) BDS-I prevented Aβ(1–42)-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 K(V)3.4 channels and restoring [Ca(2+)](i) oscillation frequency, prevented Aβ(1–42)-induced ER stress and cell suffering in astrocytes.