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Pagnon de la Vega, M., Syvänen, S., Giedraitis, V., Hooley, M., Konstantinidis, E., Meier, S. R., . . . Sehlin, D. (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications, 12(1), Article ID 22.
Open this publication in new window or tab >>Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 22Article in journal (Refereed) Published
Abstract [en]

Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Alzheimer's disease (AD), Amyloid precursor protein (APP), Amyloid-beta (A beta), PET imaging, Microglia, Astrocytes, Immunotherapy
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-523728 (URN)10.1186/s40478-024-01734-x (DOI)001158145500001 ()38317196 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationUppsala UniversitySwedish Research Council, 2016‑02120Swedish Research Council, 2021‑01083Swedish Research Council, 2021‑03524AlzheimerfondenThe Swedish Brain FoundationTorsten Söderbergs stiftelseÅhlén-stiftelsenMagnus Bergvall FoundationStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseStiftelsen Sigurd och Elsa Goljes minne
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2024-02-26 Created: 2024-02-26 Last updated: 2024-02-26Bibliographically approved
Beretta, C., Svensson, E., Dakhel, A., Zyśk, M., Hanrieder, J., Sehlin, D., . . . Erlandsson, A. (2024). Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms. Molecular and Cellular Neuroscience, 128, Article ID 103916.
Open this publication in new window or tab >>Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
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2024 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 128, article id 103916Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Alzheimer's disease, Amyloid β, Astrocytes, Aggregate
National Category
Other Medical Sciences not elsewhere specified Other Biological Topics Neurosciences
Identifiers
urn:nbn:se:uu:diva-525108 (URN)10.1016/j.mcn.2024.103916 (DOI)001175074700001 ()
Funder
Uppsala UniversitySwedish Research Council, 2021-02563Alzheimerfonden, AF-980656Åhlén-stiftelsen, 223037The Swedish Brain Foundation, FO2022-0083Stiftelsen Gamla Tjänarinnor, 2021-01171O.E. och Edla Johanssons vetenskapliga stiftelseOlle Engkvists stiftelse, 215-0399Bertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes Stiftelse
Available from: 2024-03-15 Created: 2024-03-15 Last updated: 2024-04-09Bibliographically approved
Bonvicini, G., Singh, S., Nygren, P., Xiong, M., Syvänen, S., Sehlin, D., . . . Andersson, K. G. (2024). Comparing in vitro affinity measurements of antibodies to TfR1: Surface plasmon resonance versus on-cell affinity. Analytical Biochemistry, 686, Article ID 115406.
Open this publication in new window or tab >>Comparing in vitro affinity measurements of antibodies to TfR1: Surface plasmon resonance versus on-cell affinity
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2024 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 686, article id 115406Article in journal (Refereed) Published
Abstract [en]

Despite years of utilizing the transferrin receptor 1 (TfR1) to transport large biomolecules into the brain, there is no consensus on how to optimally measure affinity to it. The aim of this study was to compare different methods for measuring the affinities of anti-TfR1 antibodies.

Antibodies 15G11, OX26 and 8D3 are known to successfully carry large biologics across the blood-brain barrier in humans, rats, and mice, respectively. The affinity to their respective species of TfR1 was measured with different surface plasmon resonance setups in Biacore and an on-cell assay.

When the antibody was captured and TfR1 was the analyte, the dissociation in Biacore was very slow. The dissociation was faster when the antibody was the analyte and TfR1 was the ligand. The Biacore setup with capture of N-terminal FLAG-tag TfR1 yielded the most similar apparent affinities as the cell assay.

In conclusion, it is important to evaluate assay parameters including assay orientation, surface capture method, and antibody format when comparing binding kinetics for TfR1 antibodies. Although it seems possible to determine relative affinities of TfR1 antibodies using the methods described here, both the FLAG-tag TfR1 capture setup and cell assays likely yield apparent affinities that are most translatable in vivo.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Transferrin receptor 1, surface plasmon resonance, on-cell affinity, method development, receptor mediated transcytosis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-508593 (URN)10.1016/j.ab.2023.115406 (DOI)001133711700001 ()38006952 (PubMedID)
Funder
EU, Horizon 2020, Marie Skłodowska-Curie grant agreement No 813528
Available from: 2023-08-03 Created: 2023-08-03 Last updated: 2024-01-15Bibliographically approved
Schlein, E., Andersson, K. G., Dallas, T., Syvänen, S. & Sehlin, D. (2024). Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody. mAbs, 16(1), Article ID 2339337.
Open this publication in new window or tab >>Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody
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2024 (English)In: mAbs, ISSN 1942-0862, E-ISSN 1942-0870, Vol. 16, no 1, article id 2339337Article in journal (Refereed) Published
Abstract [en]

Recent development of amyloid-β (Aβ)-targeted immunotherapies for Alzheimer’s disease (AD) have highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PET) ligands are well suited for this purpose as they can be directed toward the same target as the therapeutic antibody. Bispecific, brain-penetrating antibodies can achieve sufficient brain concentrations, but their slow blood clearance remains a challenge, since it prolongs the time required to achieve a target-specific PET signal. Here, two antibodies were designed based on the Aβ antibody bapineuzumab (Bapi) – one monospecific IgG (Bapi) and one bispecific antibody with an antigen binding fragment (Fab) of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3) for active, TfR-mediated transport into the brain. A variant of each antibody was designed to harbor a mutation to the neonatal Fc receptor (FcRn) binding domain, to increase clearance. Blood and brain pharmacokinetics of radiolabeled antibodies were studied in wildtype (WT) and AD mice (AppNL-G-F). The FcRn mutation substantially reduced blood half-life of both Bapi and Bapi-Fab8D3. Bapi-Fab8D3 showed high brain uptake and the brain-to-blood ratio of its FcRn mutated form was significantly higher in AppNL-G-F mice than in WT mice 12 h after injection and increased further up to 168 h. Ex vivo autoradiography showed specific antibody retention in areas with abundant Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody increases the systemic elimination and could thereby drastically reduce the time from injection to in vivo imaging.

Place, publisher, year, edition, pages
Taylor & Francis, 2024
Keywords
Alzheimer's disease (AD), amyloid-beta (a beta), bispecific antibody, blood-brain barrier (BBB), neonatal Fc receptor (FcRn), receptor mediated transcytosis (RMT)
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-527470 (URN)10.1080/19420862.2024.2339337 (DOI)001205384000001 ()38634473 (PubMedID)
Funder
AlzheimerfondenGun och Bertil Stohnes StiftelseEU, Horizon Europe, 813528The Swedish Brain FoundationKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseMagnus Bergvall FoundationStiftelsen Gamla TjänarinnorSwedish Research Council, 2021-01083Swedish Research Council, 2021-03524Åhlén-stiftelsen
Available from: 2024-05-07 Created: 2024-05-07 Last updated: 2024-05-07Bibliographically approved
Schlein, E., Rokka, J., Odell, L. R., Lopes van den Broek, S., Herth, M. M., Battisti, U. M., . . . Eriksson, J. (2024). Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET. EJNMMI Radiopharmacy and Chemistry, 9(1), Article ID 21.
Open this publication in new window or tab >>Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET
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2024 (English)In: EJNMMI Radiopharmacy and Chemistry, E-ISSN 2365-421X, Vol. 9, no 1, article id 21Article in journal (Refereed) Published
Abstract [en]

The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood-brain barrier (BBB). To overcome this challenge we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. These ligands, when radiolabelled, can be used for brain imaging with high affinity and specificity, but their long residence time in the blood and brain can be challenging for their use as PET radioligands. This could be solved by using a two-step approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a radiolabelled molecule, with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved using the inverse electron demand Diels-Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants.

In this study, two 18F-labelled tetrazines were synthesized and evaluated for their potential as agents for pre-targeted imaging, i.e. for their ability to rapidly enter the brain and then, if non-bound, be sufficiently cleared with low background retention. The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans revealed that the [18F]MeTz had the most favourable profile for an imaging agent for pre-targeting, due to its fast and homogenous brain distribution and rapid clearance from the brain.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Inverse electron demand Diels−Alder reaction IEDDA, pre-targeting, tetrazine, Alzheimer’s disease, bio-orthogonal, Fluorine-18
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-499057 (URN)10.1186/s41181-024-00250-6 (DOI)001176805900001 ()38446356 (PubMedID)
Funder
Swedish Research CouncilAlzheimerfondenTorsten Söderbergs stiftelseThe Swedish Brain FoundationHedlund foundationÅhlén-stiftelsenKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseMagnus Bergvall FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla TjänarinnorEU, Horizon 2020, 813528
Available from: 2023-03-22 Created: 2023-03-22 Last updated: 2024-04-02Bibliographically approved
Faresjö, R., Sehlin, D. & Syvänen, S. (2023). Age, dose, and binding to TfR on blood cells influence brain delivery of a TfR-transported antibody. Fluids and Barriers of the CNS, 20(1), Article ID 34.
Open this publication in new window or tab >>Age, dose, and binding to TfR on blood cells influence brain delivery of a TfR-transported antibody
2023 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 20, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

Background

Transferrin receptor 1 (TfR1) mediated brain delivery of antibodies could become important for increasing the efficacy of emerging immunotherapies in Alzheimer's disease (AD). However, age, dose, binding to TfR1 on blood cells, and pathology could influence the TfR1-mediated transcytosis of TfR1-binders across the blood–brain barrier (BBB). The aim of the study was, therefore, to investigate the impact of these factors on the brain delivery of a bispecific TfR1-transported Aβ-antibody, mAb3D6-scFv8D3, in comparison with the conventional antibody mAb3D6.

Methods

Young (3–5 months) and aged (17–20 months) WT and tg-ArcSwe mice (AD model) were injected with 125I-labeled mAb3D6-scFv8D3 or mAb3D6. Three different doses were used in the study, 0.05 mg/kg (low dose), 1 mg/kg (high dose), and 10 mg/kg (therapeutic dose), with equimolar doses for mAb3D6. The dose-corrected antibody concentrations in whole blood, blood cells, plasma, spleen, and brain were evaluated at 2 h post-administration. Furthermore, isolated brains were studied by autoradiography, nuclear track emulsion, and capillary depletion to investigate the intrabrain distribution of the antibodies, while binding to blood cells was studied in vitro using blood isolated from young and aged mice.

Results

The aged WT and tg-ArcSwe mice showed significantly lower brain concentrations of TfR-binding [125I]mAb3D6-scFv8D3 and higher concentrations in the blood cell fraction compared to young mice. For [125I]mAb3D6, no significant differences in blood or brain delivery were observed between young and aged mice or between genotypes. A low dose of [125I]mAb3D6-scFv8D3 was associated with increased relative parenchymal delivery, as well as increased blood cell distribution. Brain concentrations and relative parenchymal distribution of [125I]mAb3D6-scFv8D6 did not differ between tg-ArcSwe and WT mice at this early time point but were considerably increased compared to those observed for [125I]mAb3D6.

Conclusion

Age-dependent differences in blood and brain concentrations were observed for the bispecific antibody mAb3D6-scFv8D3 but not for the conventional Aβ antibody mAb3D6, indicating an age-related effect on TfR1-mediated brain delivery. The lowest dose of [125I]mAb3D6-scFv8D3 was associated with higher relative BBB penetration but, at the same time, a higher distribution to blood cells. Overall, Aβ-pathology did not influence the early brain distribution of the bispecific antibody. In summary, age and bispecific antibody dose were important factors determining brain delivery, while genotype was not.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
brain delivery, bispecific antibody, age, aging, transferrin receptor
National Category
Neurosciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-488406 (URN)10.1186/s12987-023-00435-2 (DOI)000985357500001 ()37170266 (PubMedID)
Funder
Uppsala UniversitySwedish Research Council, 2021-03524Swedish Research Council, 2021-01083Vinnova, 2019-00106AlzheimerfondenThe Swedish Brain FoundationTorsten Söderbergs stiftelseÅhlén-stiftelsenStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseMagnus Bergvall FoundationKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseEU, European Research Council, 807015Science for Life Laboratory, SciLifeLabKnut and Alice Wallenberg Foundation
Available from: 2023-01-13 Created: 2023-01-13 Last updated: 2024-01-17Bibliographically approved
Zielinski, M., Peralta Reyes, F. S., Gremer, L., Schemmert, S., Frieg, B., Schäfer, L. U., . . . Schröder, G. F. (2023). Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease. Nature Neuroscience, 26(12), 2073-2080
Open this publication in new window or tab >>Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease
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2023 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 26, no 12, p. 2073-2080Article in journal (Refereed) Published
Abstract [en]

The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer's disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer's disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aβ fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APPSwe and APP23 models. The tg-APPArcSwe mice showed an Aβ fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer's disease. A detailed assessment of the Aβ fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer's disease.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-526548 (URN)10.1038/s41593-023-01484-4 (DOI)001106141500001 ()37973869 (PubMedID)
Available from: 2024-04-12 Created: 2024-04-12 Last updated: 2024-06-13Bibliographically approved
Banka, V., Kelleher, A., Sehlin, D., Hultqvist, G., Sigurdsson, E. M., Syvänen, S. & Ding, Y.-S. (2023). Development of brain-penetrable antibody radioligands for in vivo PET imaging of amyloid-β and tau. Frontiers in nuclear medicine, 3, Article ID 1173693.
Open this publication in new window or tab >>Development of brain-penetrable antibody radioligands for in vivo PET imaging of amyloid-β and tau
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2023 (English)In: Frontiers in nuclear medicine, ISSN 2673-8880, Vol. 3, article id 1173693Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Alzheimer's disease (AD) is characterized by the misfolding and aggregation of two major proteins: amyloid-beta (Aβ) and tau. Antibody-based PET radioligands are desirable due to their high specificity and affinity; however, antibody uptake in the brain is limited by the blood-brain barrier (BBB). Previously, we demonstrated that antibody transport across the BBB can be facilitated through interaction with the transferrin receptor (TfR), and the bispecific antibody-based PET ligands were capable of detecting Aβ aggregates via ex vivo imaging. Since tau accumulation in the brain is more closely correlated with neuronal death and cognition, we report here our strategies to prepare four F-18-labeled specifically engineered bispecific antibody probes for the selective detection of tau and Aβ aggregates to evaluate their feasibility and specificity, particularly for in vivo PET imaging.

METHODS: We first created and evaluated (via both in vitro and ex vivo studies) four specifically engineered bispecific antibodies, by fusion of single-chain variable fragments (scFv) of a TfR antibody with either a full-size IgG antibody of Aβ or tau or with their respective scFv. Using [18F]SFB as the prosthetic group, all four 18F-labeled bispecific antibody probes were then prepared by conjugation of antibody and [18F]SFB in acetonitrile/0.1 M borate buffer solution (final pH ~ 8.5) with an incubation of 20 min at room temperature, followed by purification on a PD MiniTrap G-25 size exclusion gravity column.

RESULTS: Based on both in vitro and ex vivo evaluation, the bispecific antibodies displayed much higher brain concentrations than the unmodified antibody, supporting our subsequent F18-radiolabeling. [18F]SFB was produced in high yields in 60 min (decay-corrected radiochemical yield (RCY) 46.7 ± 5.4) with radiochemical purities of >95%, confirmed by analytical high performance liquid chromatography (HPLC) and radio-TLC. Conjugation of [18F]SFB and bispecific antibodies showed a 65%-83% conversion efficiency with radiochemical purities of 95%-99% by radio-TLC.

CONCLUSIONS: We successfully labeled four novel and specifically engineered bispecific antibodies with [18F]SFB under mild conditions with a high RCY and purities. This study provides strategies to create brain-penetrable F-18 radiolabeled antibody probes for the selective detection of tau and Aβ aggregates in the brain of transgenic AD mice via in vivo PET imaging.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
AD, Aβ, PET, [18F]SFB, antibody, blood–brain barrier, tau, transferrin receptor
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-526475 (URN)10.3389/fnume.2023.1173693 (DOI)37680310 (PubMedID)
Available from: 2024-04-11 Created: 2024-04-11 Last updated: 2024-06-13Bibliographically approved
Gustavsson, T., Metzendorf, N. G., Wik, E., Roshanbin, S., Julku, U., Chourlia, A., . . . Sehlin, D. (2023). Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease. Alzheimer's Research & Therapy, 15(1), Article ID 90.
Open this publication in new window or tab >>Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease
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2023 (English)In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 15, no 1, article id 90Article in journal (Refereed) Published
Abstract [en]

Background

Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer’s disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis.

Methods

AppNL−G−F knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens. First, to assess the acute therapeutic effect, a single antibody dose was given to 5 months old AppNL−G−F mice, with evaluation after 3 days. Second, to assess the antibodies’ ability to halt the progression of Aβ pathology, 3 months old AppNL−G−F mice received three doses during a week, with evaluation after 2 months. Reduction of RmAb158-scFv8D3 immunogenicity was explored by introducing mutations in the antibody or by depletion of CD4+ T cells. Third, to study the effects of chronic treatment, 7-month-old AppNL−G−F mice were CD4+ T cell depleted and treated with weekly antibody injections for 8 weeks, including a final diagnostic dose of [125I]RmAb158-scFv8D3, to determine its brain uptake ex vivo. Soluble Aβ aggregates and total Aβ42 were quantified with ELISA and immunostaining.

Results

Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4+ T cell depletion was used for long-term therapy. CD4+ T cell-depleted mice, chronically treated with RmAb158-scFv8D3, showed a dose-dependent increase in blood concentration of the diagnostic [125I]RmAb158-scFv8D3, while concentration was low in plasma and brain. Chronic treatment did not affect soluble Aβ aggregates, but a reduction in total Aβ42 was seen in the cortex of mice treated with both antibodies.

Conclusions

Both RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Alzheimer's disease (AD), Immunotherapy, Amyloid-beta (A beta), Monoclonal antibody, Blood-brain barrier (BBB), Transferrin receptor (TfR)-mediated transcytosis
National Category
Geriatrics Neurosciences
Identifiers
urn:nbn:se:uu:diva-504962 (URN)10.1186/s13195-023-01236-3 (DOI)000981590900003 ()37131196 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationScience for Life Laboratory, SciLifeLab
Note

Title in Web of Science: Long-term effects of immunotherapy with a brain penetrating A beta antibody in a mouse model of Alzheimer's disease

Available from: 2023-06-19 Created: 2023-06-19 Last updated: 2024-04-29Bibliographically approved
Xiong, M., Roshanbin, S., Sehlin, D., Hansen, H. D., Knudsen, G. M., Rokka, J., . . . Syvänen, S. (2023). Synaptic density in aging mice measured by [18F]SynVesT-1 PET. NeuroImage, 277, Article ID 120230.
Open this publication in new window or tab >>Synaptic density in aging mice measured by [18F]SynVesT-1 PET
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2023 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 277, article id 120230Article in journal (Refereed) Published
Abstract [en]

Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [18F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice. Wild type C57BL/6 mice divided into three age groups (4-5 months ( n = 7), 12-14 months ( n = 11), 17- 19 months ( n = 7)) were PET scanned with [18F]SynVesT-1. Brain retention of [18F]SynVesT-1 expressed as the volume of distribution (VIDIF) was calculated using an image-derived input function. Estimates of VIDIF were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [18F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers. We found that [18F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [18F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed.

Place, publisher, year, edition, pages
Elsevier BV, 2023
Keywords
Synaptic density, Aging, Positron emission tomography (PET), Mice
National Category
Radiology, Nuclear Medicine and Medical Imaging Neurosciences
Identifiers
urn:nbn:se:uu:diva-508878 (URN)10.1016/j.neuroimage.2023.120230 (DOI)001038740700001 ()37355199 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2017-02413Swedish Research Council, 2018-02715AlzheimerfondenParkinsonfondenEU, Horizon 2020, 813528Torsten Söderbergs stiftelseThe Swedish Brain FoundationKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseMagnus Bergvall Foundation
Available from: 2023-08-11 Created: 2023-08-11 Last updated: 2023-08-11Bibliographically approved
Projects
Enhanced brain delivery of antibodies for effective treatment of neurodegenerative diseases [2018-02715_VR]; Uppsala UniversityDevelopment of a neuroimaging biomarker to identify the pro-coagulant state in Alzheimer’s disease [2020-02858_VR]; Uppsala UniversityBrain penetrating antibodies for treatment of neurodegenerative disease [2021-03524_VR]; Uppsala University; Publications
Pagnon de la Vega, M., Syvänen, S., Giedraitis, V., Hooley, M., Konstantinidis, E., Meier, S. R., . . . Sehlin, D. (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications, 12(1), Article ID 22. Schlein, E., Andersson, K. G., Dallas, T., Syvänen, S. & Sehlin, D. (2024). Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody. mAbs, 16(1), Article ID 2339337.
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9430-3859

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