Physiological and biophysical factors that influence Alzheimer's disease amyloid plaque targeting of native and putrescine modified human amyloid β40

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

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Amyloid β40 (Aβ40) and its derivatives are being developed as probes for the ante-mortem diagnosis of Alzheimer's disease. Putrescine-Aβ40 (PUT-Aβ40) showed better plaque targeting than the native Aβ40, 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 Aβ40 and PUT-Aβ40. Despite better plaque-targeting ability, 125I-PUT-Aβ40 was more rapidly cleared from the systemic circulation than amyloid β40 labeled with 125I ( 125I-Aβ40) after i.v. administration in mice. The BBB permeability of both compounds was inhibited by circulating peripheral Aβ40 levels. 125I-Aβ40 but not 125I-PUT-Aβ40 was actively taken up by the mouse brain slices in vitro. Only fluorescein- Aβ40, not fluorescein-PUT-Aβ40, was localized in the brain parenchymal cells in vitro. The metabolism of 125I-Aβ40 in the brain slices was twice as great as 125I-PUT-Aβ40. 125I-Aβ40 efflux from the brain slices was saturable and found to be 5 times greater than that of 125I-PUT-Aβ40. Thioflavin-T fibrillogenesis assay demonstrated that PUT-Aβ40 has a greater propensity to form insoluble fibrils compared with Aβ40, most likely due to the ability of PUT-Aβ40 to form β sheet structure more readily than Aβ40. These results demonstrate that the inadequate plaque targeting of Aβ40 is due to cellular uptake, metabolism, and efflux from the brain parenchyma. Despite better plaque targeting of PUT-Aβ40, 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 Aβ with improved characteristics.

Original languageEnglish (US)
Pages (from-to)17-25
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number1
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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