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Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors.
- Source :
-
Cell calcium [Cell Calcium] 2010 Mar; Vol. 47 (3), pp. 264-72. Date of Electronic Publication: 2010 Jan 12. - Publication Year :
- 2010
-
Abstract
- Amyloid beta (Abeta) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which Abeta oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by Abeta. Using rat cortical neurons in culture and entorhinal-hippocampal organotypic slices, we found that Abeta oligomers significantly induced inward currents, intracellular Ca2+ increases and apoptotic cell death through a mechanism requiring NMDA and AMPA receptor activation. The massive entry of Ca2+ through NMDA and AMPA receptors induced by Abeta oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of Abeta oligomers also induced NMDA- and AMPA receptor-dependent cell death in entorhinal cortex and hippocampal slice cultures. Together, these results indicate that overactivation of NMDA and AMPA receptor, mitochondrial Ca2+ overload and mitochondrial damage underlie the neurotoxicity induced by Abeta oligomers. Hence, drugs that modulate these events can prevent from Abeta damage to neurons in Alzheimer's disease.<br /> (2009 Elsevier Ltd. All rights reserved.)
- Subjects :
- Alzheimer Disease metabolism
Alzheimer Disease pathology
Alzheimer Disease physiopathology
Amyloid beta-Peptides toxicity
Animals
Apoptosis physiology
Calcium Signaling drug effects
Cells, Cultured
Energy Metabolism physiology
Entorhinal Cortex metabolism
Hippocampus metabolism
Membrane Potential, Mitochondrial physiology
Mitochondria metabolism
Nerve Degeneration chemically induced
Nerve Degeneration physiopathology
Organ Culture Techniques
Oxidative Stress physiology
Rats
Rats, Sprague-Dawley
Receptors, AMPA metabolism
Receptors, Glutamate drug effects
Receptors, N-Methyl-D-Aspartate metabolism
Amyloid beta-Peptides metabolism
Calcium metabolism
Calcium Signaling physiology
Nerve Degeneration metabolism
Receptors, Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1532-1991
- Volume :
- 47
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell calcium
- Publication Type :
- Academic Journal
- Accession number :
- 20061018
- Full Text :
- https://doi.org/10.1016/j.ceca.2009.12.010