Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of 125I-Amyloid 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 Alz-heimer’s disease (AD) brain due to the accumulation of amyloid (A) proteins such as A40. The relationship between A40 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 amy-loid plaque formation and the potential use of A40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the 125I-A40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The 125I-A40 was significantly metabolized in the liver kidney spleen. Coadministration of exogenous A40 inhibited the plasma clearance and the uptake of 125I-A40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimina-tion from the brain. The 125I-A40 was shown to be metabo-lized within and effluxed from the brain parenchyma. The rate of efflux from APP,PS1 brain slices was substantially lower com-pared with WT brain slices. Since the A40 receptor at the BBB can be easily saturated, the blood-to-brain transport of A40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of A40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inade-quate targeting of A40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of A40 transporter at the BBB and its metabolism and efflux from the brain. Development of amyloid plaques in the extracellular space of the brain parenchyma is considered a primary event in the pathogenesis of Alzheimer’s disease (AD) (Selkoe, 2001). Amyloid plaques consist predominantly of the amyloid (A