Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of¹²⁵I-Amyloid β Protein 40 in Wild-Type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation

Abstract

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid ␤ (A␤) proteins such as A␤40. The relationship between A␤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␤40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the 125 I-A␤40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The 125 I-A␤40 was significantly metabolized in the liver kidney Ͼ spleen. Coadministration of exogenous A␤40 inhibited the plasma clearance and the uptake of 125 I-A␤40 at the bloodbrain barrier (BBB) in WT animals but did not affect its elimination from the brain. The 125 I-A␤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␤40 receptor at the BBB can be easily saturated, the blood-to-brain transport of A␤40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of A␤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␤40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of A␤40 transporter at the BBB and its metabolism and efflux from the brain.

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…The participation of LRP-1 in BBB efflux of Ab is supported by the finding that knockdown of LRP-1 in the BBB using antisense oligonucleotides causes impaired Ab efflux, accumulation of Ab in the brains of young, wild-type mice, and cognitive impairments. 54 The association of impaired Ab efflux with AD was substantiated by observations of decreased Ab efflux in rodent models of AD 55,56 as well as in aged squirrel monkeys 57 and in a small sample set of humans with AD. 58 More recently, it has become evident that other transporters in the BBB facilitating Ab efflux also become impaired in AD.…”

“…85,86 Systemic clearance of Ab is facilitated by the liver and, to a lesser extent, the kidneys and spleen. 55,87 Lipoprotein receptorrelated protein-1 was shown to be the predominant transporter that mediates clearance by the liver. The short half-life of circulating Ab (on the scale of minutes), 55,87 and the capacity of the liver to clear Ab at levels far exceeding its physiologic concentration in blood suggest that there is a biologic necessity to protect against elevations in circulating Ab.…”

“…55,87 Lipoprotein receptorrelated protein-1 was shown to be the predominant transporter that mediates clearance by the liver. The short half-life of circulating Ab (on the scale of minutes), 55,87 and the capacity of the liver to clear Ab at levels far exceeding its physiologic concentration in blood suggest that there is a biologic necessity to protect against elevations in circulating Ab. 87 This also suggests that rapid systemic clearance of Ab prevents reuptake by RAGE after efflux.…”

Clearance of Amyloid Beta Plaques from Brain of Alzheimeric Rats by Lavandula angustifolia

“…Although the animals were received Aβ intracerebroventricularly, however, via plasma clearance of Aβ, the extract can help to decrease the Aβ level in brain. Since systemic clearance of Aβ, especially by the liver, could determine the plasma levels of Aβ available for transport into the brain across the blood-brain barrier [9,15] it can be concluded that the lavender may undergo the liver clearance of Aβ. However, probable direct effect of the medicine on the Aβ plaques in the brain requires crossing the blood-brain barrier.…”

“…One of the mechanisms in removing Aβ is mediated by liver and low-density lipoprotein receptorrelated protein (LRP-1) [8,9]. LRP-1 is a receptor for uptaking Aβ through hepatic [10].…”