The Anemonia sulcata Toxin BDS-I Protects Astrocytes Exposed to Aβ1–42 Oligomers by Restoring [Ca2+]i Transients and ER Ca2+ Signaling

Abstract

Intracellular calcium concentration ([Ca2+]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 KV3.4 underlying the fast-inactivating currents, has been demonstrated in several AD models. Here, the effect of KV3.4 modulation by the marine toxin blood depressing substance-I (BDS-I) extracted from Anemonia sulcata has been studied on [Ca2+]i transients in rat primary cortical astrocytes exposed to Aβ1–42 oligomers. We showed that: (1) primary cortical astrocytes expressing KV3.4 channels displayed [Ca2+]i transients depending on the occurrence of membrane potential spikes, (2) BDS-I restored, in a dose-dependent way, [Ca2+]i transients in astrocytes exposed to Aβ1–42 oligomers (5 µM/48 h) by inhibiting hyperfunctional KV3.4 channels, (3) BDS-I counteracted Ca2+ overload into the endoplasmic reticulum (ER) induced by Aβ1–42 oligomers, (4) BDS-I prevented the expression of the ER stress markers including active caspase 12 and GRP78/BiP in astrocytes treated with Aβ1–42 oligomers, and (5) BDS-I prevented Aβ1–42-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 KV3.4 channels and restoring [Ca2+]i oscillation frequency, prevented Aβ1–42-induced ER stress and cell suffering in astrocytes.

The Antioxidant Activity of Limonene Counteracts Neurotoxicity Triggered byAβ1-42 Oligomers in Primary Cortical Neurons

“…In the present study we showed that limonene, acting on ROS production, prevented the K V 3.4 current enhancement induced by Aβ 1-42 oligomers. Of note, the increase in ROS level observed in AD is recognized to be an early biochemical event leading to the enhancement of K V 3.4 currents induced by Aβ 1-42 oligomers [32,36,40]. Therefore, consistent with our previous results, we hypothesized that a marked increase in ROS levels observed here may produce the upregulation of K V 3.4 activity also in primary cortical neurons.…”

“…In addition, in other studies K V 3.4 is reported to be an oxidation-sensitive channel since it is directly modulated by ROS increasing K V 3.4 current amplitude [41]. Importantly, we observed that K V 3.4 silencing or pharmacological inhibition with the sea anemone toxin blood depression substance-I (BDS-I) prevented Aβ 1-42 -induced insults in neurons as well as abnormal Ca 2+ signaling and ER stress in astrocytes [36,40]. Strikingly, in vivo silencing of K V 3.4 was able to reduce glial fibrillary acidic protein (GFAP) over-expression and Aβ 1-42 trimer burden in the Tg2576 mice brain, a transgenic model of AD [32].…”

“…Previously, we provided evidence that Aβ 1-42 oligomers induced a selective upregulation of K V 3.4 channels through the ROS-dependent activation of the transcription factor NF-kB [36] and that the subsequent increase of K + efflux was involved in neuronal and astrocytic damage [32,36,40]. Since the blockade of K V 3.4 appeared to be an effective strategy to counteract Aβ 1-42 -mediated caspase-3 overactivation [38,39], we here tested the hypothesis that limonene could prevent the ROS-dependent up-regulation of fastinactivating I A currents mediated by K V 3.4 in primary cortical neurons exposed to Aβ 1-42 oligomers.…”

“…Moreover, K + channels have also been involved in astroglial responses and neuroinflammation in AD [31][32][33][34]. Intriguingly, the fast inactivating K + (I A ) currents mediated through the voltage-gated K + channel K V 3.4 that contribute to the regulation of neuronal and astrocytic excitability have been implicated in AD pathology [29,32,[35][36][37][38][39][40]. Previous studies by our group demonstrated that Aβ 1-42 -induced up-regulation of K V 3.4 is implicated in caspase-3 activation and in astrocytic responses to Aβ 1-42 insult [32,35,36,[38][39][40].…”

“…Intriguingly, the fast inactivating K + (I A ) currents mediated through the voltage-gated K + channel K V 3.4 that contribute to the regulation of neuronal and astrocytic excitability have been implicated in AD pathology [29,32,[35][36][37][38][39][40]. Previous studies by our group demonstrated that Aβ 1-42 -induced up-regulation of K V 3.4 is implicated in caspase-3 activation and in astrocytic responses to Aβ 1-42 insult [32,35,36,[38][39][40]. Of note, our previous investigations showed that the ROS signaling pathway induced by Aβ 1-42 oligomers is an early biochemical event leading to the selective enhancement of K V 3.4 currents through the activation of NF-kB transcriptional factor [36].…”