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NEUROPHARMACOLOGY

Physiological and Biophysical Factors That Influence Alzheimer's Disease Amyloid Plaque Targeting of Native and Putrescine Modified Human Amyloid 40

Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology (K.K.K., G.L.C., S.S.H., E.J.G., T.M.W., J.F.P.) and Department of Biochemistry/Molecular Biology (M.R.-A.), Mayo Clinic College of Medicine, Rochester, Minnesota

Amyloid 40 (A40) and its derivatives are being developed as probes for the ante-mortem diagnosis of Alzheimer's disease. Putrescine-A40 (PUT-A40) showed better plaque targeting than the native A40, which was not solely explained by the differences in their blood-brain-barrier (BBB) permeabilities. The objective of this study was to elucidate the physiological and biophysical factors influencing the differential targeting of A40 and PUT-A40. Despite better plaque-targeting ability ¹²⁵I-PUT-A40 was more rapidly cleared from the systemic circulation than amyloid 40 labeled with ¹²⁵I (¹²⁵I-A40) after i.v. administration in mice. The BBB permeability of both compounds was inhibited by circulating peripheral A40 levels. ¹²⁵I-A40 but not ¹²⁵I-PUT-A40 was actively taken up by the mouse brain slices in vitro. Only fluorescein-A40, not fluorescein-PUT-A40, was localized in the brain parenchymal cells in vitro. The metabolism of ¹²⁵I-A40 in the brain slices was twice as great as ¹²⁵I-PUT-A40. ¹²⁵I-A40 efflux from the brain slices was saturable and found to be 5 times greater than that of ¹²⁵I-PUT-A40. Thioflavin-T fibrillogenesis assay demonstrated that PUT-A40 has a greater propensity to form insoluble fibrils compared with A40, most likely due to the ability of PUT-A40 to form sheet structure more readily than A40. These results demonstrate that the inadequate plaque targeting of A40 is due to cellular uptake, metabolism, and efflux from the brain parenchyma. Despite better plaque targeting of PUTA40, its propensity to form fibrils may render it less suitable for human use and thus allow increased focus on the development of novel derivatives of A with improved characteristics.

Address correspondence to: Joseph F. Poduslo, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail: poduslo.joseph{at}mayo.edu

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				K. K. Kandimalla, T. M. Wengenack, G. L. Curran, E. J. Gilles, and J. F. Poduslo Pharmacokinetics and Amyloid Plaque Targeting Ability of a Novel Peptide-Based Magnetic Resonance Contrast Agent in Wild-Type and Alzheimer's Disease Transgenic Mice J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 541 - 549. [Abstract] [Full Text] [PDF]