Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloidβ protein 40 in wild-type and Alzheimer's disease transgenic mice (APP, PS1) and its implications for amyloid plaque formation

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid beta (A beta) proteins such as A beta 40. The relationship between A beta 40 pharmacokinetics and its accumulation within and clearance from the brain in both wild-type (WT) and AD transgenic mice (APP,PS1) was studied to understand the mechanism of amyloid plaque formation and the potential use of A beta 40 as a probe to target and detect amyloid plaques. In both WT and APP, PS1 mice, the I-125-A beta 40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The I-125-A beta 40 was significantly metabolized in the liver >> kidney > spleen. Coadministration of exogenous A beta 40 inhibited the plasma clearance and the uptake of I-125-A beta 40 at the bloodbrain barrier (BBB) in WT animals but did not affect its elimination from the brain. The I-125-A beta 40 was shown to be metabolized within and effluxed from the brain parenchyma. The rate of efflux from APP, PS1 brain slices was substantially lower compared with WT brain slices. Since the A beta 40 receptor at the BBB can be easily saturated, the blood-to-brain transport of A beta 40 is less likely to be a primary contributor to the amyloid plaque formation in APP, PS1 mice. The decreased elimination of A beta 40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP, PS1 mice. Furthermore, inadequate targeting of A beta 40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of A beta 40 transporter at the BBB and its metabolism and efflux from the brain.