Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical.
Abeta 1-40 is a potential peptide radiopharmaceutical that could be used to image the brain Abeta amyloid of Alzheimer disease in vivo, should this peptide be made transportable through the blood-brain barrier in vivo. The blood-brain barrier transport of [ 125 I]-Abeta 1-40 in a transgenic mouse model was enabled by conjugation to the rat 8D3 monoclonal antibody to the mouse transferrin receptor. The Abeta 1-40 -8D3 conjugate is a bifunctional molecule that binds the blood-brain barrier TfR and undergoes transport into brain and binds the Abeta amyloid plaques of Alzheimer disease. App SW /Psen1 double-transgenic and littermate control mice were administered either unconjugated Abeta 1-40 or the Abeta 1-40 -8D3 conjugate intravenously, and brain scans were obtained 6 hours later. Immunocytochemical analysis showed abundant Abeta immunoreactive plaques in the brains of the App SW /Psen1 transgenic mice and there was a selective retention of radioactivity in the brains of these mice at 6 hours after intravenous administration of the conjugate. In contrast, there was no selective sequestration either of the conjugate in control littermate mouse brain or of unconjugated Abeta 1-40 in transgenic mouse brain. In conclusion, the results show that it is possible to image the Abeta amyloid burden in the brain in vivo with an amyloid imaging agent, provided the molecule is conjugated to a blood-brain barrier drug-targeting system.
Lee
Hwa Jeong
HJ
Department of Medicine, UCLA School of Medicine, Los Angeles, California 90024, USA.
Zhang
Yun
Y
Zhu
Chunni
C
Duff
Karen
K
Pardridge
William M
WM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D000922:Immunotoxins; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1; D011990:Receptors, Transferrin / Q000378:metabolism; D012016:Reference Values; D019809:Streptavidin
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D011990:Receptors, Transferrin; C078592:amyloid beta-protein (1-40); D019809:Streptavidin