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
✍ Scribed by Elisabete Ferreiro; Catarina R. Oliveira; Cláudia Pereira
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 133 KB
- Volume
- 76
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
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 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.