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Involvement of endoplasmic reticulum Ca 2+ release through ryanodine and inositol 1,4,5‐triphosphate receptors in the neurotoxic effects induced by the amyloid‐β peptide
Author(s) -
Ferreiro Elisabete,
Oliveira Catarina R.,
Pereira Cláudia
Publication year - 2004
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20135
Subject(s) - thapsigargin , ryanodine receptor , endoplasmic reticulum , inositol , receptor , chemistry , microbiology and biotechnology , inositol trisphosphate receptor , inositol phosphate , biology , medicine , biochemistry
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 Ca 2+ 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 Ca 2+ homeostasis, may contribute to Aβ toxicity. To elucidate the involvement of deregulation of ER Ca 2+ homeostasis in neuronal death induced by Aβ peptides, we have performed a comparative study using the synthetic peptides Aβ 25–35 or Aβ 1–40 and thapsigargin, a selective inhibitor of Ca 2+ uptake into the ER. Incubation of cortical neurons with thapsigargin (2.5 μM) increased the intracellular Ca 2+ 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 (Aβ 25–35 , 25 μM; Aβ 1–40 , 0.5 μM), we observed a significant increase in [Ca 2+ ] i , in caspase‐3‐like activity, and in number of neurons exhibiting apoptotic morphology. The role of ER Ca 2+ release through ryanodine receptors (RyR) or inositol 1,4,5‐trisphosphate receptors (IP 3 R) in Aβ neurotoxicity has been also investigated. Dantrolene and xestospongin C, inhibitors of ER Ca 2+ release through RyR or IP 3 R, were able to prevent the increase in [Ca 2+ ] i and the activation of caspase‐3 and to protect partially against apoptosis induced by treatment with Aβ 25–35 or Aβ 1–40 . In conclusion, our results demonstrate that the release of Ca 2+ from the ER, mediated by both RyR and IP 3 R, 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 Ca 2+ homeostasis. © 2004 Wiley‐Liss, Inc.