Specific Uptake of an Amyloid-β Protofibril-Binding Antibody-Tracer in AβPP Transgenic Mouse Brain

Article type: Research Article

Authors: Magnusson, Kristina^{a; 1} | Sehlin, Dag^{a; 1} | Syvänen, Stina^a | Svedberg, Marie M.^{a; b} | Philipson, Ola^a | Söderberg, Linda^c | Tegerstedt, Karin^c | Holmquist, Mats^c | Gellerfors, Pär^c | Tolmachev, Vladimir^d | Antoni, Gunnar^{b; e} | Lannfelt, Lars^a | Hall, Håkan^{b; *} | Nilsson, Lars N.G.^{a; f}

Affiliations: [a] Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden | [b] Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden | [c] BioArctic Neuroscience AB, Stockholm, Sweden | [d] Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden | [e] PET Centre, Uppsala University Hospital, Uppsala, Sweden | [f] Department of Pharmacology, Oslo University and Oslo University Hospital, Oslo, Norway

Correspondence: [*] Correspondence to: Håkan Hall, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Dag Hammarskjölds väg 14C, SE-751 83 Uppsala, Sweden. Tel.: +46 707 22 48 02; Fax: +46 18 471 5307; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [125I]mAb158, which binds to Aβ protofibrils with high affinity. [125I]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-β protein precursor (AβPP) as shown ex vivo. This was in contrast to [125I]mAb-Ly128 which does not bind to Aβ. The uptake of intraperitoneally-administered [125I]mAb158 into the brain was age- and time-dependent, and saturable in AβPP transgenic mice with modest Aβ deposition. Brain uptake was also found in young AβPP transgenic mice that were devoid of Aβ deposits, suggesting that [125I]mAb158 targets soluble Aβ protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of Aβ protofibrils.

Keywords: Alzheimer's disease, amyloid-β protofibrils, antibody, brain uptake, positron emission tomography, transgenic mice

DOI: 10.3233/JAD-130029

Journal: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 29-40, 2013