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Reduction of calcium release from the endoplasmic reticulum could only provide partial neuroprotection against beta‐amyloid peptide toxicity
Author(s) -
Suen KaChun,
Lin KimFung,
Elyaman Wassim,
So KwokFai,
ChuenChung Chang Raymond,
Hugon Jacques
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2003.02259.x
Subject(s) - neuroprotection , endoplasmic reticulum , neurotoxicity , unfolded protein response , calcium , microbiology and biotechnology , amyloid beta , chemistry , calcium signaling , cytochrome c , calcium metabolism , peptide , apoptosis , toxicity , mitochondrion , biology , biochemistry , pharmacology , signal transduction , organic chemistry
Beta‐amyloid (Aβ) peptide has been suggested to play important roles in the pathogenesis of Alzheimer's disease (AD). Aβ peptide neurotoxicity was shown to induce disturbance of cellular calcium homeostasis. However, whether modulation of calcium release from the endoplasmic reticulum (ER) can protect neurons from Aβ toxicity is not clearly defined. In the present study, Aβ peptide‐triggered ER calcium release in primary cortical neurons in culture is modulated by Xestospongin C, 2‐aminoethoxydiphenyl borate or FK506. Our results showed that reduction of ER calcium release can partially attenuate Aβ peptide neurotoxicity evaluated by LDH release, caspase‐3 activity and quantification of apoptotic cells. While stress signals associated with perturbations of ER functions such as up‐regulation of GRP78 was significantly attenuated, other signaling machinery such as activation of caspase‐7 transmitting death signals from ER to other organelles could not be altered. We further provide evidence that molecular signaling in mitochondria play also a significant role in determining neuronal apoptosis because Aβ peptide‐triggered activation of caspase‐9 was not significantly reduced by attenuating ER calcium release. Our results suggest that neuroprotective strategies aiming at reducing Aβ toxicity should include molecular targets linked to ER perturbations associated with ER calcium release as well as mitochondrial stress.