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Antibody-Based In Vivo PET Imaging Detects Amyloid-beta Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition [Elektronisk resurs]

Meier, Silvio R. (författare)
Syvänen, Stina (författare)
Hultqvist, Greta, 1980- (författare)
Fang, Xiaotian T. (författare)
Roshanbin, Sahar, 1984- (författare)
Lannfelt, Lars (författare)
Neumann, Ulf (författare)
Sehlin, Dag, 1976- (författare)
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet (utgivare)
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet (utgivare)
Publicerad: SOC NUCLEAR MEDICINE INC, 2018
Engelska.
Ingår i: Journal of Nuclear Medicine. - 0161-5505. ; 59:12, 1885-1891
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  • 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

Medical and Health Sciences  (hsv)
Clinical Medicine  (hsv)
Radiology, Nuclear Medicine and Medical Imaging  (hsv)
Medicin och hälsovetenskap  (hsv)
Klinisk medicin  (hsv)
Radiologi och bildbehandling  (hsv)

Genre

government publication  (marcgt)

Indexterm och SAB-rubrik

Alzheimer's disease
positron emission tomography (PET)
antibody-based radioligand
BACE-1 inhibitor NB-360
amyloid-beta
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