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In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

Nabuurs RJ, Rutgers KS, Welling MM, Metaxas A, de Backer ME, Rotman M, Bacskai BJ, van Buchem MA, van der Maarel SM, van der Weerd L - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. R.J.A.Nabuurs@LUMC.nl

ABSTRACT
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.

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Related in: MedlinePlus

Blood clearance.These graphs represent the blood half lives of tagged 99mTc-ni3A and -pa2H (A), and untagged DTPA(111In)-pa2H (B) in APP/PS1 mice and wildtype littermates. Data is shown as percentage of injected dose per gram of blood (%ID/g) over time. Based upon this plot the clearance is suggested to respectively consist of a fast and a slow phase, or only a single phase.
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pone-0038284-g002: Blood clearance.These graphs represent the blood half lives of tagged 99mTc-ni3A and -pa2H (A), and untagged DTPA(111In)-pa2H (B) in APP/PS1 mice and wildtype littermates. Data is shown as percentage of injected dose per gram of blood (%ID/g) over time. Based upon this plot the clearance is suggested to respectively consist of a fast and a slow phase, or only a single phase.

Mentions: Half lives were determined by fitting a one or a two phase exponential decay model based on blood obtained from both tail vein and cardiac puncture at several time points after intravenous bolus injection of 2 µg radiolabeled VHH in 12–14 month old APP/PS1 mice and wildtype littermates, as depicted in Figure 2. Please note that DTPA(111In)-pa2H was produced without any additional peptide tags.


In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

Nabuurs RJ, Rutgers KS, Welling MM, Metaxas A, de Backer ME, Rotman M, Bacskai BJ, van Buchem MA, van der Maarel SM, van der Weerd L - PLoS ONE (2012)

Blood clearance.These graphs represent the blood half lives of tagged 99mTc-ni3A and -pa2H (A), and untagged DTPA(111In)-pa2H (B) in APP/PS1 mice and wildtype littermates. Data is shown as percentage of injected dose per gram of blood (%ID/g) over time. Based upon this plot the clearance is suggested to respectively consist of a fast and a slow phase, or only a single phase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366949&req=5

pone-0038284-g002: Blood clearance.These graphs represent the blood half lives of tagged 99mTc-ni3A and -pa2H (A), and untagged DTPA(111In)-pa2H (B) in APP/PS1 mice and wildtype littermates. Data is shown as percentage of injected dose per gram of blood (%ID/g) over time. Based upon this plot the clearance is suggested to respectively consist of a fast and a slow phase, or only a single phase.
Mentions: Half lives were determined by fitting a one or a two phase exponential decay model based on blood obtained from both tail vein and cardiac puncture at several time points after intravenous bolus injection of 2 µg radiolabeled VHH in 12–14 month old APP/PS1 mice and wildtype littermates, as depicted in Figure 2. Please note that DTPA(111In)-pa2H was produced without any additional peptide tags.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. R.J.A.Nabuurs@LUMC.nl

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus