All Title Author
Keywords Abstract

PLOS ONE  2012 

In Vivo Detection of Amyloid-β Deposits Using Heavy Chain Antibody Fragments in a Transgenic Mouse Model for Alzheimer's Disease

DOI: 10.1371/journal.pone.0038284

Full-Text   Cite this paper   Add to My Lib

Abstract:

This study investigated the in vivo properties of two heavy chain antibody fragments (VHH), 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 VHH in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled VHH by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All VHH showed rapid renal clearance (10–20 min). Twenty-four hours post-injection 99mTc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for 99mTc-ni3A or DTPA(111In)-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ 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 Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that VHH 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.

References

[1]  Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118: 5–36. doi:10.1007/s00401-009-0532-1.
[2]  Smith EE, Greenberg SM (2009) Beta-amyloid, blood vessels, and brain function. Stroke 40: 2601–2606. doi:10.1161/STROKEAHA.108.536839.
[3]  Weller RO, Preston SD, Subash M, Carare RO (2009) Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease. Alzheimers Res Ther 1: 6. doi:10.1186/alzrt6.
[4]  Jicha GA (2009) Is passive immunization for Alzheimer's disease ‘alive and well’ or ‘dead and buried’? Expert Opin Biol Ther 9: 481–491. doi:10.1517/14712590902828285.
[5]  Greenberg SM, Bacskai BJ, Hyman BT (2003) Alzheimer disease's double-edged vaccine. Nat Med 9: 389–390. doi:10.1038/nm847.
[6]  Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, et al. (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9: 119–128. doi:10.1016/S1474-4422(09)70299-6.
[7]  Frisoni GB, Fox NC, Jack CR Jr, Scheltens P, Thompson PM (2010) The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol 6: 67–77. doi:10.1038/nrneurol.2009.215.
[8]  Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, et al. (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 62: 229–234. doi:10.1002/ana.21164.
[9]  Rutgers KS, van Remoortere A, van Buchem MA, Verrips CT, Greenberg SM, et al. (2009) Differential recognition of vascular and parenchymal beta amyloid deposition. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.11.012.
[10]  Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, et al. (1993) Naturally occurring antibodies devoid of light chains. Nature 363: 446–448. doi:10.1038/363446a0.
[11]  Harmsen MM, De Haard HJ (2007) Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol 77: 13–22. doi:10.1007/s00253-007-1142-2.
[12]  Rutgers KS, Nabuurs RJ, van den Berg SA, Schenk GJ, Rotman M, et al. (2011) Transmigration of beta amyloid specific heavy chain antibody fragments across the in vitro blood-brain barrier. Neuroscience. doi:10.1016/j.neuroscience.2011.05.076.
[13]  Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, et al. (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17: 157–165.
[14]  Welling MM, Paulusma-Annema A, Balter HS, Pauwels EK, Nibbering PH (2000) Technetium-99m labelled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur J Nucl Med 27: 292–301.
[15]  Welling MM, Korsak A, Gorska B, Oliver P, Mikolajczak R, et al. (2005) Kit with technetium-99m labelled antimicrobial peptide UBI 29–41 for specific infection detection. Journal of Labelled Compounds & Radiopharmaceuticals 48: 683–691. doi:10.1002/jlcr.961.
[16]  Klunk WE, Bacskai BJ, Mathis CA, Kajdasz ST, McLellan ME, et al. (2002) Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropathol Exp Neurol 61: 797–805.
[17]  Skoch J, Dunn A, Hyman BT, Bacskai BJ (2005) Development of an optical approach for noninvasive imaging of Alzheimer's disease pathology. J Biomed Opt 10: 11007. doi:10.1117/1.1846075.
[18]  Robbins EM, Betensky RA, Domnitz SB, Purcell SM, Garcia-Alloza M, et al. (2006) Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease. J Neurosci 26: 365–371. doi:10.1523/JNEUROSCI.3854-05.2006.
[19]  Wadghiri YZ, Sigurdsson EM, Wisniewski T, Turnbull DH (2005) Magnetic resonance imaging of amyloid plaques in transgenic mice. Methods Mol Biol 299: 365–379.
[20]  Natte R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, et al. (2001) Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol 50: 765–772.
[21]  Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115: 5–38. doi:10.1007/s00401-007-0312-8.
[22]  Guntert A, Dobeli H, Bohrmann B (2006) High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience 143: 461–475. doi:10.1016/j.neuroscience.2006.08.027.
[23]  van Groen T, Kiliaan AJ, Kadish I (2006) Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice. Neurobiol Dis 23: 653–662. doi:10.1016/j.nbd.2006.05.010.
[24]  Bussiere T, Bard F, Barbour R, Grajeda H, Guido T, et al. (2004) Morphological characterization of Thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Abeta immunotherapy on their clearance. Am J Pathol 165: 987–995.
[25]  Richardson JA, Burns DK (2002) Mouse models of Alzheimer's disease: a quest for plaques and tangles. ILAR J 43: 89–99.
[26]  Adlard PA, Bush AI (2006) Metals and Alzheimer's disease. J Alzheimers Dis 10: 145–163.
[27]  Leskovjan AC, Lanzirotti A, Miller LM (2009) Amyloid plaques in PSAPP mice bind less metal than plaques in human Alzheimer's disease. Neuroimage 47: 1215–1220. doi:10.1016/j.neuroimage.2009.05.063.
[28]  Gainkam LO, Huang L, Caveliers V, Keyaerts M, Hernot S, et al. (2008) Comparison of the biodistribution and tumor targeting of two 99mTc-labeled anti-EGFR nanobodies in mice, using pinhole SPECT/micro-CT. J Nucl Med 49: 788–795. doi:10.2967/jnumed.107.048538.
[29]  Huang L, Muyldermans S, Saerens D (2010) Nanobodies(R): proficient tools in diagnostics. Expert Rev Mol Diagn 10: 777–785. doi:10.1586/erm.10.62.
[30]  Behr TM, Goldenberg DM, Becker W (1998) Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations. Eur J Nucl Med 25: 201–212.
[31]  Muruganandam A, Tanha J, Narang S, Stanimirovic D (2002) Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood-brain barrier endothelium. FASEB J 16: 240–242. doi:10.1096/fj.01-0343fje.
[32]  Abulrob A, Sprong H, Van Bergen en HP, Stanimirovic D (2005) The blood-brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 95: 1201–1214. doi:10.1111/j.1471-4159.2005.03463.x.
[33]  Coppieters K, Dreier T, Silence K, de Haard H, Lauwereys M, et al. (2006) Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis. Arthritis Rheum 54: 1856–1866. doi:10.1002/art.21827.
[34]  Tijink BM, Laeremans T, Budde M, Stigter-van WM, Dreier T, et al. (2008) Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology. Mol Cancer Ther 7: 2288–2297. doi:10.1158/1535-7163.MCT-07-2384.
[35]  Koffie RM, Farrar CT, Saidi LJ, William CM, Hyman BT, et al. (2011) Nanoparticles enhance brain delivery of blood-brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging. Proc Natl Acad Sci U S A 108: 18837–18842. doi:10.1073/pnas.1111405108.
[36]  Chartier A, Raz V, Sterrenburg E, Verrips CT, van der Maarel SM, et al. (2009) Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo. Hum Mol Genet 18: 1849–1859. doi:10.1093/hmg/ddp101.
[37]  Dumoulin M, Last AM, Desmyter A, Decanniere K, Canet D, et al. (2003) A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature 424: 783–788. doi:10.1038/nature01870.
[38]  Lafaye P, Achour I, England P, Duyckaerts C, Rougeon F (2009) Single-domain antibodies recognize selectively small oligomeric forms of amyloid beta, prevent Abeta-induced neurotoxicity and inhibit fibril formation. Mol Immunol 46: 695–704. doi:10.1016/j.molimm.2008.09.008.
[39]  Verheesen P, de Kluiver A, van Koningsbruggen S, de Brij M, De Haard HJ, et al. (2006) Prevention of oculopharyngeal muscular dystrophy-associated aggregation of nuclear polyA-binding protein with a single-domain intracellular antibody. Hum Mol Genet 15: 105–111. doi:10.1093/hmg/ddi432.
[40]  Stijlemans B, Conrath K, Cortez-Retamozo V, van Xong H, Wyns L, et al. (2004) Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies. African trypanosomes as paradigm. J Biol Chem 279: 1256–1261. doi:10.1074/jbc.M307341200.
[41]  Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, et al. (2005) Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci 25: 10598–10606. doi:10.1523/JNEUROSCI.2990-05.2005.

Full-Text

comments powered by Disqus

Contact Us

service@oalib.com

QQ:3279437679

微信:OALib Journal