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Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation.
J Pharmacol Exp Ther 2005; 313(3):1370-8JP

Abstract

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid beta (Abeta) proteins such as Abeta40. The relationship between Abeta40 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 Abeta40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the (125)I-Abeta40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The (125)I-Abeta40 was significantly metabolized in the liver kidney > spleen. Coadministration of exogenous Abeta40 inhibited the plasma clearance and the uptake of (125)I-Abeta40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimination from the brain. The (125)I-Abeta40 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 Abeta40 receptor at the BBB can be easily saturated, the blood-to-brain transport of Abeta40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of Abeta40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of Abeta40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of Abeta40 transporter at the BBB and its metabolism and efflux from the brain.

Authors+Show Affiliations

Molecular Neurobiology Laboratory, Department of Neurobiology, Neuroscience, and Biohemistry/Molecular Biology, Mayo Clinic College of Medicine, MN 55905, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15743932

Citation

Kandimalla, Karunya K., et al. "Pharmacokinetic Analysis of the Blood-brain Barrier Transport of 125I-amyloid Beta Protein 40 in Wild-type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation." The Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 3, 2005, pp. 1370-8.
Kandimalla KK, Curran GL, Holasek SS, et al. Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation. J Pharmacol Exp Ther. 2005;313(3):1370-8.
Kandimalla, K. K., Curran, G. L., Holasek, S. S., Gilles, E. J., Wengenack, T. M., & Poduslo, J. F. (2005). Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation. The Journal of Pharmacology and Experimental Therapeutics, 313(3), pp. 1370-8.
Kandimalla KK, et al. Pharmacokinetic Analysis of the Blood-brain Barrier Transport of 125I-amyloid Beta Protein 40 in Wild-type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation. J Pharmacol Exp Ther. 2005;313(3):1370-8. PubMed PMID: 15743932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation. AU - Kandimalla,Karunya K, AU - Curran,Geoffry L, AU - Holasek,Silvina S, AU - Gilles,Emily J, AU - Wengenack,Thomas M, AU - Poduslo,Joseph F, Y1 - 2005/03/02/ PY - 2005/3/4/pubmed PY - 2005/7/15/medline PY - 2005/3/4/entrez SP - 1370 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 313 IS - 3 N2 - Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid beta (Abeta) proteins such as Abeta40. The relationship between Abeta40 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 Abeta40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the (125)I-Abeta40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The (125)I-Abeta40 was significantly metabolized in the liver kidney > spleen. Coadministration of exogenous Abeta40 inhibited the plasma clearance and the uptake of (125)I-Abeta40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimination from the brain. The (125)I-Abeta40 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 Abeta40 receptor at the BBB can be easily saturated, the blood-to-brain transport of Abeta40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of Abeta40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of Abeta40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of Abeta40 transporter at the BBB and its metabolism and efflux from the brain. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15743932/Pharmacokinetic_analysis_of_the_blood_brain_barrier_transport_of_125I_amyloid_beta_protein_40_in_wild_type_and_Alzheimer's_disease_transgenic_mice__APPPS1__and_its_implications_for_amyloid_plaque_formation_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15743932 DB - PRIME DP - Unbound Medicine ER -