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Preclinical PET ima...
Preclinical PET imaging of Alzheimer's disease progression
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- Fang, Xiaotian T., 1990- (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap,Geriatrics
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- Syvänen, Stina (preses)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Sehlin, Dag (preses)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Lannfelt, Lars (preses)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Haaparanta-Solin, Merja, Professor (opponent)
- University of Turku, Turku PET Centre, MediCity/PET Preclinical Laboratory, Finland
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(creator_code:org_t)
- ISBN 9789151301518
- Uppsala : Acta Universitatis Upsaliensis, 2017
- Engelska 59 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1395
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Abstract
Ämnesord
Stäng
- Amyloid PET imaging with [11C]PIB enabled detection of Aβ for the first time in vivo. However, [11C]PIB is a small molecule that binds only the insoluble Aβ plaque. Rather, the soluble Aβ aggregates are considered the cause of Alzheimer’s disease (AD). As such, a more sensitive and specific PET tracer is needed for tracking longitudinal AD pathology.Soluble Aβ aggregates likely interact with the metabotropic glutamate receptor 5 (mGluR5) to cause neurotoxic effects. However, with [11C]ABP688 PET we were unable to detect aberrant mGluR5 binding in AD mouse models, although we find elevated mGluR5 protein levels with immunoblotting.Antibodies are highly specific large molecules that can bind specifically to soluble Aβ aggregates, thus they can be a good marker for AD pathology. Unfortunately, due to their large size they cannot cross the blood-brain barrier (BBB). However, it is possible to shuttle antibodies into the brain by taking advantage of endogenous transporter systems on the BBB. By creating bispecific antibodies binding both to soluble Aβ aggregates and to the transferrin receptor (BBB target), we successfully transported the antibody into the brain and could visually detect soluble Aβ aggregates with PET.Recombinant expression further improved and optimized antibody design, creating smaller bispecific antibody-based constructs that had better pharmacokinetic properties allowing for earlier PET scanning (1 day instead of 3), and more sensitive signal.Lastly, using TCO-tetrazine click chemistry, we indirectly labeled our antibodies with fluorine-18, and could successfully perform PET already 11 h post-injection with a fluorine-18 labeled antibody.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- 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
- transgenic mice
- PET
- antibody-based tracer
- mGluR5
- ABP688
- di-scFv
- amyloid-β
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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