Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model

Findings from genetic, animal model, and human studies support the observation that accumulation of the beta-amyloid ( A beta) 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 A beta clearance. We have developed a novel microimmunoelectrode ( MIE) to study the kinetics of A beta clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in A beta levels in the brains of living mice. Extracellular, interstitial fluid ( ISF) A beta levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of A beta(40) in the ISF are relatively stable and begin to decline within minutes of blocking A beta production with a gamma-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of A beta, resulted in significant prolongation of A beta(40) half- life, but only in the latter phase of A beta clearance from the ISF.