Findings from genetic, animal model, and human studies support the observation that accumulation of the ß-amyloid (Aß) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aß clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aß clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aß levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aß levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aß40 in the ISF are relatively stable and begin to decline within minutes of blocking Aß production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aß, resulted in significant prolongation of Aß40 half-life, but only in the latter phase of Aß clearance from the ISF.