Protofibrils of amyloid beta-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 beta-protein (Abeta) 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 Abeta(1-42) PFs induce reversible, Ca(2+)-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 microM 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 Ca(2+) 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.
Ye
Chian P
CP
Department of Neurology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Selkoe
Dennis J
DJ
Hartley
Dean M
DM
D000200:Action Potentials / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D004622:Embryo, Mammalian; D005110:Extracellular Space / Q000737:chemistry; D007424:Intracellular Fluid / Q000737:chemistry; D019579:Neocortex / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D051381:Rats
D016229:Amyloid beta-Peptides; D024642:Potassium Channels, Voltage-Gated