Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model.
JOURNAL OF EXPERIMENTAL MEDICINE(2016)
摘要
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.
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