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Antibody-Based In V...
Antibody-Based In Vivo PET Imaging Detects Amyloid-beta Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition
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- Meier, Silvio R. (författare)
- Uppsala universitet,Geriatrik
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- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik
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- Hultqvist, Greta, 1980- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Fang, Xiaotian T. (författare)
- Uppsala universitet,Geriatrik
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- Roshanbin, Sahar, 1984- (författare)
- Uppsala universitet,Geriatrik
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- Lannfelt, Lars (författare)
- Uppsala universitet,Geriatrik,BioArctic AB, Stockholm, Sweden
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- Neumann, Ulf (författare)
- Novartis Inst BioMed Res, Neurosci Res, Basel, Switzerland
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- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- 2018-05-31
- 2018
- Engelska.
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 59:12, s. 1885-1891
- Relaterad länk:
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https://doi.org/10.2...
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https://uu.diva-port... (primary) (Raw object)
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http://jnm.snmjourna...
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https://urn.kb.se/re...
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https://doi.org/10.2...
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Abstract
Ämnesord
Stäng
- Visualization of amyloid-beta (A beta) pathology with PET has become an important tool for making a specific clinical diagnosis of Alzheimer disease (AD). However, the available amyloid PET radioligands, such as C-11-Pittsburgh compound B, reflect levels of insoluble A beta plaques but do not capture soluble and protofibrillar A beta forms. Furthermore, the plaque load appears to be fairly static during clinical stages of AD and may not be affected by A beta-reducing treatments. The aim of the present study was to investigate whether a novel PET radioligand based on an antibody directed toward soluble aggregates of A beta can be used to detect changes in A beta levels during disease progression and after treatment with a beta-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, a model of A beta pathology) aged between 7 and 16 mo underwent PET with the A beta protofibril-selective radioligand I-124-RmAb158-scFv8D3 (where RmAb is recombinant mouse monoclonal antibody and scFv is single-chain variable fragment) to follow progression of A beta pathology in the brain. A second set of tg-ArcSwe mice, aged 10 mo, were treated with the BACE-1 inhibitor NB-360 for 3 mo and compared with an untreated control group. A third set of tg-ArcSwe mice, also aged 10 mo, underwent PET as a baseline group. Brain tissue was isolated after PET to determine levels of A beta by ELISA and immunohistochemistry. Results: The concentration of I-124-RmAb158-scFv8D3, as measured in vivo with PET, increased with age and corresponded well with the ex vivo autoradiography and A beta immunohistochemistry results. Mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals and were similar to the baseline animals. The decreased I-124-RmAb158-scFv8D3 concentrations in NB-360-treated mice, as quantified with PET, corresponded well with the decreased A beta levels measured in postmortem brain. Conclusion: Several treatments for AD are in phase 2 and 3 clinical trials, but the possibility of studying treatment effects in vivo on the important, nonfibrillar, forms of A beta is limited. This study demonstrated the ability of the A beta protofibril-selective radioligand I-124-RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Nyckelord
- Alzheimer's disease
- positron emission tomography (PET)
- antibody-based radioligand
- BACE-1 inhibitor NB-360
- amyloid-beta
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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