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

Karunya K. Kandimalla, Geoffry L. Curran, Silvina S. Holasek, Emily J. Gilles, Thomas M. Wengenack, Joseph F. Poduslo

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid β (Aβ) proteins such as Aβ40. The relationship between Aβ40 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 Aβ40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the 125I- Aβ40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The 125I-Aβ40 was significantly metabolized in the liver ⋙ kidney > spleen. Coadministration of exogenous Aβ40 inhibited the plasma clearance and the uptake of 125I-Aβ40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimination from the brain. The 125I-Aβ40 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 Aβ40 receptor at the BBB can be easily saturated, the blood-to-brain transport of Aβ40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of Aβ40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of Aβ40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of Aβ40 transporter at the BBB and its metabolism and efflux from the brain.

Original languageEnglish (US)
Pages (from-to)1370-1378
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number3
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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