Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets.
Detection of intracerebral targets with imaging probes is challenging due to the non-permissive nature of blood-brain barrier (BBB). The present work describes two novel single-domain antibodies (VHHs or nanobodies) that specifically recognize extracellular amyloid deposits and intracellular tau neurofibrillary tangles, the two core lesions of Alzheimer's disease (AD). Following intravenous administration in transgenic mouse models of AD, in vivo real-time two-photon microscopy showed gradual extravasation of the VHHs across the BBB, diffusion in the parenchyma and labeling of amyloid deposits and neurofibrillary tangles. Our results demonstrate that VHHs can be used as specific BBB-permeable probes for both extracellular and intracellular brain targets and suggest new avenues for therapeutic and diagnostic applications in neurology.
Institut Pasteur, CITECH, Plateforme d'Ingénierie des Anticorps, 75724 Paris Cedex 15, France; Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, F-75013 Paris, France; Inserm U 1127, Paris, France; CNRS UMR 7225, Paris, France; ICM, Paris, France; Université Paris Descartes, Paris 5, France.
Tengfei
T
Li
Institut Pasteur, Unité de Chimie des Biomolécules, 75724 Paris Cedex 15, France; CNRS UMR 3523, 75724 Paris Cedex 15, France; Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), MIRCen, F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Matthias
M
Vandesquille
Institut Pasteur, Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France.
Fani
F
Koukouli
Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, F-75013 Paris, France; Inserm U 1127, Paris, France; CNRS UMR 7225, Paris, France; ICM, Paris, France; Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), MIRCen, F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Clémence
C
Dudeffant
Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, F-75013 Paris, France; Inserm U 1127, Paris, France; CNRS UMR 7225, Paris, France; ICM, Paris, France.
Ihsen
I
Youssef
Institut Pasteur, CITECH, Plateforme d'Ingénierie des Anticorps, 75724 Paris Cedex 15, France.
Pascal
P
Lenormand
Institut Pasteur, Unité de Chimie des Biomolécules, 75724 Paris Cedex 15, France; CNRS UMR 3523, 75724 Paris Cedex 15, France.
Christelle
C
Ganneau
Institut Pasteur, Neurobiologie intégrative des systèmes cholinergiques, CNRS UMR 3571, Paris, France.
Uwe
U
Maskos
F. Hoffmann-La Roche AG, Pharmaceutical Research and Early Development, NORD DTA, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
Christian
C
Czech
F. Hoffmann-La Roche AG, Pharmaceutical Research and Early Development, NORD DTA, Roche Innovation Center Basel, CH-4070 Basel, Switzerland.
Fiona
F
Grueninger
Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, F-75013 Paris, France; Inserm U 1127, Paris, France; CNRS UMR 7225, Paris, France; ICM, Paris, France.
Charles
C
Duyckaerts
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), MIRCen, F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Marc
M
Dhenain
Institut Pasteur, Unité de Chimie des Biomolécules, 75724 Paris Cedex 15, France; CNRS UMR 3523, 75724 Paris Cedex 15, France.
Sylvie
S
Bay
Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, F-75013 Paris, France; Inserm U 1127, Paris, France; CNRS UMR 7225, Paris, France; ICM, Paris, France.
Benoît
B
Delatour
Institut Pasteur, CITECH, Plateforme d'Ingénierie des Anticorps, 75724 Paris Cedex 15, France. Electronic address: pierre.lafaye@pasteur.fr.
Pierre
P
Lafaye
D061605:Administration, Intravenous; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002161:Camelids, New World / Q000276:immunology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008853:Microscopy / Q000379:methods; D016874:Neurofibrillary Tangles / Q000276:immunology*; D058225:Plaque, Amyloid / Q000276:immunology*; D061905:Single-Domain Antibodies / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
D061905:Single-Domain Antibodies
Abeta; Alzheimer's disease; Blood-brain barrier; In vivo imaging; Tau; VHH