Amyloid beta peptide modulates the activity of acid-sensing ion

Deposition of amyloid beta 1-42aa (A-beta) peptides plays acritical role in the pathology of Alzheimer disease (AD), aneurodegenerative disorder characterized by progressivelearning and memory lose. The mechanism underlying A-beta -induced learning/memory deficit is, however, not fullyunderstood. Previously, we demonstrated that bath applicationof A-beta (100 nM) inhibits the amplitude and slows theactivation of acid-sensing ion channels, a novel family of proton-gated cation channels recently shown to be essential for anormal learning/memory function in mice. This finding provideda potential new mechanism for the effect of A-beta inlearning/memory loses associated with AD patients.Here, we demonstrate that A-beta has a similar effect on ASICcurrents in postnatal neurons, as in prenatal neurons. Theeffect of A-beta on ASIC-current was more pronounced inpostnatal neurons but it tends to be reversible. In contrast, theeffect in prenatal neurons was less dramatic but was longerlasting. Presence of A-beta 1-42aa in the intracellular solutioncould not significantly alter the amplitude or kinetics of theASIC current; however, it partially blocked the effect of A-betasubsequently applied in the bath solution. Imidazole, aninhibitor of A-beta induced channel formation, was unable toprevent or reverse the effects of A-beta on the kinetics of ASICcurrent.In addition to A-beta 1-42aa, we examined the effect oftruncated peptides on the ASIC current. Bath perfusion of Abeta1-9aa did not significantly reduce the amplitude or slowdown the activation of the ASIC current (n=5). In contrast,bath perfusion of A-beta 11-25aa significantly increased the τ-activation (127% ± 6.49 of control, n=6, p <0.01). A-beta 33-40aa, a C-terminal domain of A-beta, did not alter the ASICcurrentamplitude or τ-activation. Surprisingly, it reduced thedesensitization time-constant (87.50% ± 4.99 of control, n=4,p <0.05).Advanced molecular and physiological experiments arecurrently in progress in our laboratories to further investigatethe detailed mechanisms involved in A-beta and ASICinteraction.