Soluble β-amyloid oligomers alter biophysical properties of Kv1.3 channels

Abstract

The aggregation of amyloid peptides in brain tissue is a hallmark of Alzheimer's disease. Amyloid beta (Aβ) exists in several assembly states, which may play different physiological or pathophysiological roles. The effects of Aβ on voltage-dependent ion channels in neurons and microglia were implicated in early stages of neurodegeneration. We tested the effect of soluble oligomers (Aβ1-42) of amyloid precursor protein (APP) on voltage-dependent potassium channels Kv1.3. Potassium current was measured during whole-cell recording from L929 cells, stably expressing Kv1.3. Acute application of Aβ1-42 reversibly reduced peak current amplitudes and affected kinetics of current activation, inactivation and deactivation in a voltage- and a dose-dependent manner. The time constant of K+ current activation during depolarizing voltage pulses from the holding membrane potential of −80 mV was reduced by Aβ1-42 at low (<10 mV) voltages, but was not changed at higher voltages. Slow C-type inactivation of K+ current was significantly faster in the presence of Aβ1-42 with the effect being most prominent at −20 mV (lowest voltage measured) and diminishing with increasing voltage. The time constant of K+ current deactivation was significantly reduced by Aβ1-42, and the effect progressively increased with voltage increase. Under the same conditions, the voltage sensitivity of Kv1.3 conductance was not significantly changed by Aβ1-42. Our results reveal acute effects of biologically active soluble β-amyloid oligomers on voltage-dependent potassium channels Kv1.3. Faster inactivation and deactivation of K+ current in the presence of Aβ could impair regulation of the membrane potential, ultimately leading to pathophysiological changes in the cell.Supported by the Hillblom Foundation.