In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.
This study investigated the in vivo properties of two heavy chain antibody fragments (V(H)H), ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(H)H in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled V(H)H by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All V(H)H showed rapid renal clearance (10-20 min). Twenty-four hours post-injection (99m)Tc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for (99m)Tc-ni3A or DTPA((111)In)-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ was confirmed for both fluorescently labeled V(H)H, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both V(H)H showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that V(H)H detect Aβ deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aβ deposits.
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. R.J.A.Nabuurs@LUMC.nl
Rob J A
RJ
Nabuurs
Kim S
KS
Rutgers
Mick M
MM
Welling
Athanasios
A
Metaxas
Maaike E
ME
de Backer
Maarten
M
Rotman
Brian J
BJ
Bacskai
Mark A
MA
van Buchem
Silvère M
SM
van der Maarel
Louise
L
van der Weerd
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology*; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006207:Half-Life; D006801:Humans; D007128:Immunoglobulin Fragments / Q000097:blood / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology*; D011485:Protein Binding; D013045:Species Specificity; D014018:Tissue Distribution / Q000276:immunology
D016229:Amyloid beta-Peptides; D007128:Immunoglobulin Fragments; D007143:Immunoglobulin Heavy Chains