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Title: In Vivo Detection of Amyloid-\(\beta\) Deposits Using Heavy Chain Antibody Fragments in a Transgenic Mouse Model for Alzheimer's Disease
Authors: Nabuurs, Rob J. A.;Rutgers, Kim S.;Welling, Mick M.;Metaxas, Athanasios;de Backer, Maaike E.;Rotman, Maarten;van Buchem, Mark A.;van der Maarel, Silvère M.;van der Weerd, Louise;Bacskai, Brian
subject: Biology;Neuroscience;Neuroimaging;Medicine;Neurology;Dementia;Alzheimer Disease;Neurodegenerative Diseases;Radiology
Year: 2012
Publisher: Public Library of Science
Description: 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-\(\beta\) 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 A\(\beta\) 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 A\(\beta\) was confirmed for both fluorescently labeled VHH, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both VHH showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular A\(\beta\). Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that (V\(_H\)H) detect A\(\beta\) 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 A\(\beta\) deposits.
Standard no: Nabuurs, Rob J. A., Kim S. Rutgers, Mick M. Welling, Athanasios Metaxas, Maaike E. de Backer, Maarten Rotman, Brian J. Bacskai, Mark A. van Buchem, Silvère M. van der Maarel, and Louise van der Weerd. 2012. In vivo detection of amyloid-\(\beta\) deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease. PLoS ONE 7(6): e38284.
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