Apolipoprotein E4 suppresses delayed-rectifier potassium channels in membrane patches excised from hippocampal neurons

Recent studies show a clear association between Alzheimer's disease (AD) and the apolipoprotein E epsilon 4 allele (APOE4). The mechanisms underlying apoE4-mediated detrimental effects have not been well-clarified. The present study investigates possible effects of apoE4 on the delayed-rectifier potassium (IK) channels in inside-out membrane patches excised from rat hippocampal neurons. Acute application of apoE4 (0.5 microM) to the inside of the membrane patches markedly and reversibly suppressed the single IK channel activities. The average open probability and open frequency of IK channels decreased by (92.6+/-7.1)% and (88.6+/-3.2)%, respectively. The mean open time of IK channels decreased by (81.6+/-6.7)%, and the mean closed-time of them increased by 6.9+/-1.9 fold. Meanwhile, the mean current amplitude of IK channels was not significantly affected. In contrast, application of apolipoprotein A (apoA, 0.5 microM), another member of apolipoprotein family with similar molecular weight and amino acid sequence to apoE4, did not exhibit any effects on IK currents. These results indicate that apoE4 molecules can rapidly suppress the activities of IK channels in hippocampal neurons when they act on the inner side of the neuronal membrane. We propose that the overproduction of apoE4 in neurons may suppress normal IK channel activities and thus be responsible for the late-developed neuronal damages related to the pathogenesis of AD.