ACTIVATION OF K-ACTIVITY BY SECRETED BETA-AMYLOID-PRECURSOR PROTEIN( CHANNELS AND SUPPRESSION OF NEURONAL)

THE Alzheimer's beta-amyloid precursor protein (beta-APP) is widely ex pressed in neural cells, and in neurons secreted forms of beta-APP (sA PPs) are released from membrane-spanning holo-beta APP in an activity- dependent manner(1,2). Secreted APPs can modulate neurite outgrowth, s ynaptogenesis, synaptic plasticity and cell survival(3,9); a signal tr ansduction mechanism of sAPPs may involve modulation of intracellular calcium levels ([Ca2+](i))(4,10). Here we use whole-cell perforated pa tch and single-channel patch-clamp analysis of hippocampal neurons to demonstrate that sAPPs suppress action potentials and hyperpolarize ne urons by activating high-conductance, charybdotoxin-sensitive K+ chann els. Activation of K+ channels by sAPPs was mimicked by a cyclic GMP a nalogue and sodium nitroprusside and blocked by an antagonist of cGMP- dependent kinase and a phosphatase inhibitor, suggesting that the effe ct is mediated by cGMP and protein dephosphorylation. Calcium imaging studies indicate that activation of K+ channels mediates the ability o f sAPPs to decrease [Ca-2](i). Modulation of neuronal excitability may be a major mechanism by which beta-APP regulates developmental and sy naptic plasticity in the nervous system.