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Blood-Brain Barrier Integrity in a Mouse Model of Alzheimer’s Disease With or Without Acute 3D6 Immunotherapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (tPKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 143, p. 1-9Article in journal (Refereed) Published
Abstract [en]

The blood-brain barrier (BBB) is suggested to be compromised in Alzheimer's disease (AD). The concomitant presence of vascular amyloid beta (AD) pathology, so called cerebral amyloid angiopathy (CAA), also predisposes impairment of vessel integrity. Additionally, immunotherapy against A beta may lead to further damage of the BBB. To what extent this affects the BBB passage of molecules is debated. The current study aimed to investigate BBB integrity to large molecules in transgenic mice displaying abundant A beta pathology and age matched wild type animals, with or without acute anti-A beta antibody treatment. Animals were administered a single i.v. injection of PBS or 3D6 (10 mg/kg), i.e. the murine version of the clinically investigated A beta antibody bapineuzumab, supplemented with [(125)]3D6. Three days post injections, a 4 kDa FITC and a 150 kDa Antonia Red dextran were administered i.v. to all animals. After termination, fluorescent detection in brain and serum was used for the calculation of dextran brain-to-blood concentration ratios. Further characterization of antibody fate and the presence of CAA were investigated using radioactivity measurements and Congo red staining. BBB passage of large molecules was equally low in wild type and transgenic mice, suggesting an intact BBB despite A beta pathology. Neither was the BBB integrity affected by acute 3D6 treatment. However, CAA was confirmed in the transgenes and local antibody accumulations were observed in the brain, indicating CAA-antibody interactions. The current study shows that independently of A beta pathology or acute 3D6 treatment, the BBB is intact, without extensive permeability to large molecules, including the 3D6 antibody.

Place, publisher, year, edition, pages
2018. Vol. 143, p. 1-9
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-347199DOI: 10.1016/j.neuropharm.2018.09.001ISI: 000453493200001PubMedID: 30201212OAI: oai:DiVA.org:uu-347199DiVA, id: diva2:1193721
Funder
Swedish Research Council, 2017-02413Magnus Bergvall FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla TjänarinnorAvailable from: 2018-03-27 Created: 2018-03-27 Last updated: 2019-01-11Bibliographically approved
In thesis
1. Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
Open this publication in new window or tab >>Translational Aspects of Blood-Brain Barrier Transport and Brain Distribution of Drugs in Health and Disease
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A high unmet medical need in the area of CNS diseases coincides with high failure rates in CNS drug development. Efficient treatment of CNS disease is constrained by limited entrance of drugs into the brain owing to the blood-brain barrier (BBB), which separates brain from blood. Insufficient inter-species translation and lack of methods to evaluate therapeutic, unbound, drug concentrations in human brain also contribute to development failure. Further disease related changes in BBB properties and tissue composition raise a concern of altered drug neuropharmacokinetics (neuroPK) during disease. This calls for the evaluation of translational aspects of neuroPK parameters in health and disease, and exploration of strategies for neuroPK translations between rodents and humans.

Positron emission tomography (PET) enables corresponding PK analysis in various species, although being restricted to measuring total, i.e. both unbound and nonspecifically bound, drug concentrations. However, the current work shows that PET can be used for the estimation of unbound, active, brain concentrations and for assessment of drug BBB transport, if compensation is made for intra-brain drug distribution and binding. Adapted PET designs could be applied in humans where rat estimates of drug intra-brain distribution may be used with reasonable accuracy for concentration conversions in healthy humans, but preferably not in Alzheimer’s disease (AD) patients. As shown in this thesis, a high variability in nonspecific drug tissue binding was observed in AD compared to rats and human controls that might lead to unacceptable bias of outcome values if used in PET. Furthermore, heterogeneity in drug tissue binding among brain regions in both rodents and humans was detected and must be considered in regional investigations of neuroPK. By the use of transgenic animal models of amyloid beta and alpha-synuclein pathology, the work further suggests that the BBB is able to uphold sufficient capacity for the transport of small molecular drugs and integrity towards large molecules despite the presence of hallmarks representative of neurodegenerative diseases.

This thesis work provides insight into neurodegenerative disease impact on neuroPK and contributes with translational strategies for neuroPK evaluation from preclinical investigations to the clinic, aimed to aid drug development and optimal disease management.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 254
Keywords
Blood-brain barrier, Neurovascular unit, Pharmacokinetics, Neurodegenerative disease, Drug transport, Brain tissue binding, Positron emission tomography, Brain regions
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-347204 (URN)978-91-513-0294-2 (ISBN)
Public defence
2018-05-18, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-10-08

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Gustafsson, SofiaRoshanbin, SaharHultqvist, GretaHammarlund-Udenaes, MargaretaSehlin, DagSyvänen, Stina

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