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- Title
Cytotoxicity of Intracellular Aβ<sub>42</sub> Amyloid Oligomers Involves Ca<sup>2+</sup> Release from the Endoplasmic Reticulum by Stimulated Production of Inositol Trisphosphate.
- Authors
Demuro, Angelo; Parker, Ian
- Abstract
Oligomeric forms of β-amyloid (Aβ) peptides associated with Alzheimer's disease (AD) disrupt cellular Ca2+ regulation by liberating Ca2+ into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular Aβ42 by imaging Ca2+ responses to injections of Aβ oligomers into Xenopus oocytes. Two types of signal were observed: (1) local, "channel-like" transients dependent on extracellular Ca2+ influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; and (2) local transients and global Ca2+ waves, resembling Ca2+ puffs and waves mediated by inositol trisphosphate (IP3). The latter responses were suppressed by antagonists of the IP3 receptor (caffeine and heparin), pretreatment with the Gi/0-protein inhibitor per-tussis toxin, and pretreatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP3 production and consequent liberation of Ca2+ from the endoplasmic reticulum by intracellular Aβ oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP3 receptor/channels.
- Subjects
CELL-mediated cytotoxicity; OLIGOMERS; CALCIUM channels; ENDOPLASMIC reticulum; INOSITOL trisphosphate; ALZHEIMER'S disease
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 9, p3824
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4367-12.2013