Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures
Protofibrils (PFs) are recently described intermediate assemblies formed during the fibrillogenesis of amyloidogenic proteins and may play an important pathogenic role in Parkinson’s and Alzheimer’s disease (AD). Here we show for the first time that amyloid β-protein (Aβ) attenuation of specific K+...
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| Format: | Article |
| Language: | English |
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Elsevier
2003-08-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996103000688 |
| _version_ | 1818721411042115584 |
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| author | Chian P Ye Dennis J Selkoe Dean M Hartley |
| author_facet | Chian P Ye Dennis J Selkoe Dean M Hartley |
| author_sort | Chian P Ye |
| collection | DOAJ |
| description | Protofibrils (PFs) are recently described intermediate assemblies formed during the fibrillogenesis of amyloidogenic proteins and may play an important pathogenic role in Parkinson’s and Alzheimer’s disease (AD). Here we show for the first time that amyloid β-protein (Aβ) attenuation of specific K+ currents is dependent on the aggregation state; PFs inhibit K+ currents, whereas low-molecular-weight assemblies have no effect. Using patch clamp analysis in whole cell current-clamp mode, we showed that at low nanomolar concentrations Aβ1–42 PFs induce reversible, Ca2+-dependent increases in spontaneous action potentials and membrane depolarizations. The low nanomolar PF concentrations used, the instantaneous responses observed, and the reversibility of the effect all suggest that PFs may bind to specific channels or membrane proteins. Switching to voltage-clamp mode, we found that PFs at 1–2 μM can inhibit specifically the 4AP-sensitive K+ currents, A-type and D-type, but not other outward or inward rectifying K+ channels. Finally, we show that a consequence of PF-induced membrane activity is an increase in intracellular Ca2+ spikes that are dependent on synaptic connections in the neural network formed in culture. Our data strongly support the concept that PFs can induce subtle synaptic alterations that may underlie early symptoms of AD. |
| first_indexed | 2024-12-17T20:38:18Z |
| format | Article |
| id | doaj.art-97c334f889fe4296abf800428fc2a82a |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T20:38:18Z |
| publishDate | 2003-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-97c334f889fe4296abf800428fc2a82a2022-12-21T21:33:23ZengElsevierNeurobiology of Disease1095-953X2003-08-01133177190Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical culturesChian P Ye0Dennis J Selkoe1Dean M Hartley2Departments of Neurology and Medicine, Harvard Medical School, and the Center for Neurologic Diseases and Division of Endocrinology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USADepartments of Neurology and Medicine, Harvard Medical School, and the Center for Neurologic Diseases and Division of Endocrinology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USADepartments of Neurology and Medicine, Harvard Medical School, and the Center for Neurologic Diseases and Division of Endocrinology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USAProtofibrils (PFs) are recently described intermediate assemblies formed during the fibrillogenesis of amyloidogenic proteins and may play an important pathogenic role in Parkinson’s and Alzheimer’s disease (AD). Here we show for the first time that amyloid β-protein (Aβ) attenuation of specific K+ currents is dependent on the aggregation state; PFs inhibit K+ currents, whereas low-molecular-weight assemblies have no effect. Using patch clamp analysis in whole cell current-clamp mode, we showed that at low nanomolar concentrations Aβ1–42 PFs induce reversible, Ca2+-dependent increases in spontaneous action potentials and membrane depolarizations. The low nanomolar PF concentrations used, the instantaneous responses observed, and the reversibility of the effect all suggest that PFs may bind to specific channels or membrane proteins. Switching to voltage-clamp mode, we found that PFs at 1–2 μM can inhibit specifically the 4AP-sensitive K+ currents, A-type and D-type, but not other outward or inward rectifying K+ channels. Finally, we show that a consequence of PF-induced membrane activity is an increase in intracellular Ca2+ spikes that are dependent on synaptic connections in the neural network formed in culture. Our data strongly support the concept that PFs can induce subtle synaptic alterations that may underlie early symptoms of AD.http://www.sciencedirect.com/science/article/pii/S0969996103000688 |
| spellingShingle | Chian P Ye Dennis J Selkoe Dean M Hartley Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures Neurobiology of Disease |
| title | Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures |
| title_full | Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures |
| title_fullStr | Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures |
| title_full_unstemmed | Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures |
| title_short | Protofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures |
| title_sort | protofibrils of amyloid β protein inhibit specific k currents in neocortical cultures |
| url | http://www.sciencedirect.com/science/article/pii/S0969996103000688 |
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