Enhancement of outward potassium current may participate in β-amyloid peptide-induced cortical neuronal death

In light of recent evidence implicating the upregulation of outward K⁺ current in mediating several forms of neuronal apoptosis, we tested the hypothesis that such an upregulation might specifically contribute to the pathogenesis of β-amyloid peptide (Aβ)-induced neuronal death. Exposure to Aβ fragment 25-35 (20 μM) or 1-42 (20 μM) enhanced the delayed rectifier K⁺ current I(K), shifting its activation voltage relationship toward hyperpolarized levels and increasing maximal conductance, but did not affect the transient K⁺ current I(A) or charybdotoxin-sensitive BK current. Reducing I(K) by adding the channel blocker tetraethylammonium (TEA, 5 mM)or raising extracellular K⁺ to 25 mM attenuated Aβ-induced neuronal death, even in the presence of nifedipine or gadolinium to block associated increases in Ca²⁺ influx. The I(A) blocker 4-aminopyridine (4-AP, 5 mM) and the Cl^- channel blocker anthracene-9-carboxylic acid (ACA, 500 μM) were not neuroprotective. These data raise the intriguing possibility that manipulations aimed at reducing outward K⁺ current may provide an approach to reducing neuronal degeneration in patients with Alzheimer's disease.