Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5‐triphosphate receptors in the neurotoxic effects induced by the amyloid‐β peptide

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Abstract
Studies with in‐vitro‐cultured neurons treated with amyloid‐β (Aβ) peptides demonstrated neuronal loss by apoptosis that is due, at least in part, to the perturbation of intracellular Ca2+ homeostasis. In addition, it was shown that an endoplasmic reticulum (ER)‐specific apoptotic pathway mediated by caspase‐12, which is activated upon the perturbation of ER Ca2+ homeostasis, may contribute to Aβ toxicity. To elucidate the involvement of deregulation of ER Ca2+ homeostasis in neuronal death induced by Aβ peptides, we have performed a comparative study using the synthetic peptides Aβ25–35 or Aβ1–40 and thapsigargin, a selective inhibitor of Ca2+ uptake into the ER. Incubation of cortical neurons with thapsigargin (2.5 μM) increased the intracellular Ca2+ levels and activated caspase‐3, leading to a significant increase in the number of apoptotic cells. Similarly, upon incubation of cortical cultures with the Aβ peptides (Aβ25–35, 25 μM; Aβ1–40, 0.5 μM), we observed a significant increase in [Ca2+]i, in caspase‐3‐like activity, and in number of neurons exhibiting apoptotic morphology. The role of ER Ca2+ release through ryanodine receptors (RyR) or inositol 1,4,5‐trisphosphate receptors (IP3R) in Aβ neurotoxicity has been also investigated. Dantrolene and xestospongin C, inhibitors of ER Ca2+ release through RyR or IP3R, were able to prevent the increase in [Ca2+]i and the activation of caspase‐3 and to protect partially against apoptosis induced by treatment with Aβ25–35 or Aβ1–40. In conclusion, our results demonstrate that the release of Ca2+ from the ER, mediated by both RyR and IP3R, is involved in Aβ toxicity and can contribute, together with the activation of other intracellular neurotoxic mechanisms, to Aβ‐induced neuronal death. This study suggests that Aβ accumulation may have a key role in the pathogenesis of AD as a result of deregulation of ER Ca2+ homeostasis.