Amyloid β oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors

被引:283
作者
Alberdi, Elena [1 ]
Victoria Sanchez-Gomez, Ma [1 ]
Cavaliere, Fabio [1 ]
Pérez-Samartín, Alberto [1 ]
Luis Zugaza, Jose [2 ]
Trullas, Ramon [3 ]
Domercq, Maria [1 ]
Matute, Carlos [1 ]
机构
[1] Univ Basque Country, Dept Neurociencias, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-48940 Leioa, Spain
[2] CIC Biogune, E-48160 Derio, Spain
[3] Inst Invest Biomed August Pi & Sunyer, Consejo Super Invest Cient, Inst Invest Biomed Barcelona,Neurobiol Unit, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08036 Barcelona, Spain
关键词
Amyloid beta oligomers; Ca2+ dysregulation; Mitochondrial damage; NMDA receptors; AMPA receptors; Alzheimer disease; ALZHEIMERS-DISEASE; A-BETA; OXIDATIVE STRESS; WHITE-MATTER; IN-VIVO; MECHANISM; NEURODEGENERATION; EXCITOTOXICITY; NEUROTOXICITY; MITOCHONDRIA;
D O I
10.1016/j.ceca.2009.12.010
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Amyloid beta (A beta) oligomers accumulate in brain tissue of Alzheimer disease patients and are related to pathogenesis. The precise mechanisms by which A beta oligomers cause neurotoxicity remain unresolved. In this study, we investigated the role of ionotropic glutamate receptors on the intracellular Ca2+ overload caused by A beta. Using rat cortical neurons in culture and entorhinal-hippocampal organotypic slices, we found that A beta 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 A beta oligomers caused mitochondrial dysfunction as indicated by mitochondrial Ca2+ overload, oxidative stress and mitochondrial membrane depolarization. Importantly, chronic treatment with nanomolar concentration of A beta 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 A beta oligomers. Hence, drugs that modulate these events can prevent from A beta damage to neurons in Alzheimer's disease. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:264 / 272
页数:9
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