Characterisation of the binding of amyloid imaging tracers to rodent Abeta fibrils and rodent-human Abeta co-polymers.
Despite the application of amyloid imaging agents such as PIB, SB13, and FDDNP in Alzheimer's disease (AD) patients, the successful use of these agents in transgenic mice models of AD has not been reported to date. As a first step in understanding the behaviour of these ligands in transgenic models of AD, we have investigated in a series of in vitro ligand binding assays the interaction of selected agents, including PIB, FDDNP, SB13, and BSB, with amyloid fibrils produced from rodent Abeta(1-40) (roAbeta) peptide. The data indicate that the ligand binding affinities together with the pattern and number of binding sites on the roAbeta fibrils are broadly conserved with that reported previously for human Abeta(1-40) (huAbeta) fibrils. However, characterisation of huAbeta fibrils formed in the presence of increasing amounts of roAbeta (1, 5, 10% w/w) demonstrated a dose-dependent reduction in the number of high affinity [(3)H]Me-BTA-1 binding sites such that at the highest amount of roAbeta the specific signal was reduced by approximately 95%. These studies suggest that (i) the presence of small amounts of roAbeta in huAbeta fibrils has the potential to cause subtle ultrastructural alterations in the polymers and (ii) the weak binding signal observed in vivo in the transgenic mouse models of AD may in part be due to the decreased number of high affinity binding sites on the Abeta fibrils.
Ye
Liang
L
GlaxoSmithKline Research and Development, Translational Medicine and Genetics, Addenbrookes Hospital, Cambridge, UK.
Morgenstern
Jennifer L
JL
Lamb
Jonathan R
JR
Lockhart
Andrew
A
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000378:metabolism; D014316:Tritium
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D008024:Ligands; D013844:Thiazoles; D014316:Tritium; C009462:thioflavin T