Physiological and biophysical factors that influence Alzheimer's disease amyloid plaque targeting of native and putrescine modified human amyloid beta40.
Amyloid beta40 (Abeta40) and its derivatives are being developed as probes for the ante-mortem diagnosis of Alzheimer's disease. Putrescine-Abeta40 (PUT-Abeta40) showed better plaque targeting than the native Abeta40, 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 Abeta40 and PUT-Abeta40. Despite better plaque-targeting ability 125I-PUT-Abeta40 was more rapidly cleared from the systemic circulation than amyloid beta40 labeled with 125I (125I-Abeta40) after i.v. administration in mice. The BBB permeability of both compounds was inhibited by circulating peripheral Abeta40 levels. 125I-Abeta40 but not 125I-PUT-Abeta40 was actively taken up by the mouse brain slices in vitro. Only fluorescein-Abeta40, not fluorescein-PUT-Abeta40, was localized in the brain parenchymal cells in vitro. The metabolism of 125I-Abeta40 in the brain slices was twice as great as 125I-PUT-Abeta40. 125I-Abeta40 efflux from the brain slices was saturable and found to be 5 times greater than that of 125I-PUT-Abeta40. Thioflavin-T fibrillogenesis assay demonstrated that PUT-Abeta40 has a greater propensity to form insoluble fibrils compared with Abeta40, most likely due to the ability of PUT-Abeta40 to form beta sheet structure more readily than Abeta40. These results demonstrate that the inadequate plaque targeting of Abeta40 is due to cellular uptake, metabolism, and efflux from the brain parenchyma. Despite better plaque targeting of PUTAbeta40, 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 Abeta with improved characteristics.
Molecular Neurobiology Laboratory, Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Karunya K
KK
Kandimalla
Geoffry L
GL
Curran
Silvina S
SS
Holasek
Emily J
EJ
Gilles
Thomas M
TM
Wengenack
Marina
M
Ramirez-Alvarado
Joseph F
JF
Poduslo
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000187:drug effects / Q000502:physiology*; D011700:Putrescine / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D011700:Putrescine