The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death
Alzheimer’s disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ<sub>1-42</sub> structure and toxicity is of major interest. NMDA receptors (NMDAR) are...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/12315 |
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| author | Aiste Jekabsone Silvija Jankeviciute Katryna Pampuscenko Vilmante Borutaite Ramune Morkuniene |
| author_facet | Aiste Jekabsone Silvija Jankeviciute Katryna Pampuscenko Vilmante Borutaite Ramune Morkuniene |
| author_sort | Aiste Jekabsone |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ<sub>1-42</sub> structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ<sub>1-42</sub> species—small oligomers, large oligomers, insoluble fibrils, and monomers—were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ<sub>1-42</sub> oligomers induced a concentration- and time-dependent increase in intracellular Ca<sup>2+</sup> and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca<sup>2+</sup> nor viability was significantly affected by larger Aβ<sub>1-42</sub> species or monomers. In addition, the small Aβ<sub>1-42</sub> oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ<sub>1-42</sub>-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy. |
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| last_indexed | 2024-03-11T00:25:19Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4be05f16f07347f79b2adab1819d4c7a2023-11-18T23:03:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124151231510.3390/ijms241512315The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial DeathAiste Jekabsone0Silvija Jankeviciute1Katryna Pampuscenko2Vilmante Borutaite3Ramune Morkuniene4Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, LithuaniaAlzheimer’s disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ<sub>1-42</sub> structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ<sub>1-42</sub> species—small oligomers, large oligomers, insoluble fibrils, and monomers—were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ<sub>1-42</sub> oligomers induced a concentration- and time-dependent increase in intracellular Ca<sup>2+</sup> and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca<sup>2+</sup> nor viability was significantly affected by larger Aβ<sub>1-42</sub> species or monomers. In addition, the small Aβ<sub>1-42</sub> oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ<sub>1-42</sub>-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.https://www.mdpi.com/1422-0067/24/15/12315Alzheimer’s diseaseamyloid-βmicrogliaNMDA receptorsmitochondrial ROScell death |
| spellingShingle | Aiste Jekabsone Silvija Jankeviciute Katryna Pampuscenko Vilmante Borutaite Ramune Morkuniene The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death International Journal of Molecular Sciences Alzheimer’s disease amyloid-β microglia NMDA receptors mitochondrial ROS cell death |
| title | The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death |
| title_full | The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death |
| title_fullStr | The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death |
| title_full_unstemmed | The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death |
| title_short | The Role of Intracellular Ca<sup>2+</sup> and Mitochondrial ROS in Small Aβ<sub>1-42</sub> Oligomer-Induced Microglial Death |
| title_sort | role of intracellular ca sup 2 sup and mitochondrial ros in small aβ sub 1 42 sub oligomer induced microglial death |
| topic | Alzheimer’s disease amyloid-β microglia NMDA receptors mitochondrial ROS cell death |
| url | https://www.mdpi.com/1422-0067/24/15/12315 |
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