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  1. Book ; Online ; Thesis: Characterization of the new htau-KI mouse model for Alzheimer’s disease with a focus on the role of immune cells during progressing cerebral amyloidosis

    Barendrecht, Susan [Verfasser] / Posern, Guido [Gutachter] / Eckmann, Christian R. [Gutachter] / Wirths, Oliver [Gutachter]

    2021  

    Author's details Susan Barendrecht ; Gutachter: Guido Posern, Christian R. Eckmann, Oliver Wirths
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language English
    Publisher Universitäts- und Landesbibliothek Sachsen-Anhalt
    Publishing place Halle (Saale)
    Document type Book ; Online ; Thesis
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  2. Article ; Online: A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice.

    Barendrecht, Susan / Schreurs, An / Geissler, Stefanie / Sabanov, Victor / Ilse, Victoria / Rieckmann, Vera / Eichentopf, Rico / Künemund, Anja / Hietel, Benjamin / Wussow, Sebastian / Hoffmann, Katrin / Körber-Ferl, Kerstin / Pandey, Ravi / Carter, Gregory W / Demuth, Hans-Ulrich / Holzer, Max / Roßner, Steffen / Schilling, Stephan / Preuss, Christoph /
    Balschun, Detlef / Cynis, Holger

    Alzheimer's research & therapy

    2023  Volume 15, Issue 1, Page(s) 16

    Abstract: Background: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the ... ...

    Abstract Background: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay.
    Methods: We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer's-like pathology, synaptic transmission, and behavior.
    Results: The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI.
    Conclusion: In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.
    MeSH term(s) Mice ; Humans ; Animals ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Alzheimer Disease/pathology ; tau Proteins/genetics ; tau Proteins/metabolism ; Amyloidosis ; Brain/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism
    Chemical Substances Amyloid beta-Peptides ; tau Proteins ; Amyloid beta-Protein Precursor
    Language English
    Publishing date 2023-01-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2506521-X
    ISSN 1758-9193 ; 1758-9193
    ISSN (online) 1758-9193
    ISSN 1758-9193
    DOI 10.1186/s13195-022-01144-y
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  3. Article ; Online: A novel human tau knock-in mouse model reveals interaction of Abeta and human tau under progressing cerebral amyloidosis in 5xFAD mice

    Barendrecht, Susan / Schreurs, An / Geißler, Stefanie / Sabanov, Victor / Ilse, Victoria / Rieckmann, Vera / Eichentopf, Rico / Künemund, Anja / Hietel, Benjamin / Wussow, Sebastian / Hoffmann, Katrin / Körber-Ferl, Kerstin / Pandey, Ravi / Carter, Gregory W. / Demuth, Hans-Ulrich / Holzer, Max / Roßner, Steffen / Schilling, Stephan / Preuss, Christoph /
    Balschun, Detlef / Cynis, Holger

    2023  

    Abstract: Background: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second ...

    Abstract Background: Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods: We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results: The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion: In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

    15
    Keywords Alzheimer's disease ; Animal model ; Tau ; Knock-in ; Amyloid ; Gene expression ; Synaptic function
    Subject code 572
    Language English
    Publishing country de
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Targeting isoaspartate-modified Aβ rescues behavioral deficits in transgenic mice with Alzheimer's disease-like pathology.

    Gnoth, Kathrin / Piechotta, Anke / Kleinschmidt, Martin / Konrath, Sandra / Schenk, Mathias / Taudte, Nadine / Ramsbeck, Daniel / Rieckmann, Vera / Geissler, Stefanie / Eichentopf, Rico / Barendrecht, Susan / Hartlage-Rübsamen, Maike / Demuth, Hans-Ulrich / Roßner, Steffen / Cynis, Holger / Rahfeld, Jens-Ulrich / Schilling, Stephan

    Alzheimer's research & therapy

    2020  Volume 12, Issue 1, Page(s) 149

    Abstract: Background: Amyloid β (Aβ)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post- ... ...

    Abstract Background: Amyloid β (Aβ)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified Aβ peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such Aβ variants have been initiated. Modified Aβ represents a small fraction of deposited material in plaques compared to pan-Aβ epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified Aβ (isoD7-Aβ) and tested a lead antibody molecule in 5xFAD mice.
    Methods: This work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. Aβ peptides, containing L-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-Aβ monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-Aβ ELISA as well as different non-modified Aβ ELISA. For antibody treatment studies, 12 mg/kg anti-isoD7-Aβ antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38 weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze.
    Results: Our advanced antibody K11 showed a K
    Conclusions: The present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified Aβ, the results highlight the crucial role of modified Aβ peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.
    MeSH term(s) Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor/genetics ; Animals ; Disease Models, Animal ; Isoaspartic Acid ; Mice ; Mice, Transgenic
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Isoaspartic Acid
    Language English
    Publishing date 2020-11-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2506521-X
    ISSN 1758-9193 ; 1758-9193
    ISSN (online) 1758-9193
    ISSN 1758-9193
    DOI 10.1186/s13195-020-00719-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Targeting isoaspartate-modified Av rescues behavioral deficits in transgenic mice with Alzheimer's disease-like pathology

    Gnoth, Kathrin / Piechotta, Anke / Kleinschmidt, Martin / Hartlage-Rübsamen, Maike / Schenk, Mathias / Taudte, Nadine / Ramsbeck, Daniel / Roßner, Steffen / Geißler, Stefanie / Konrath, Sandra / Nykiel, Vera / Eichentopf, Rico / Demuth, Hans-Ulrich / Barendrecht, Susan / Cynis, Holger / Rahfeld, Jens-Ulrich / Schilling, Stephan

    2020  

    Abstract: Background: Amyloid v (Av)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post- ... ...

    Abstract Background: Amyloid v (Av)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified Av peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such Av variants have been initiated. Modified Av represents a small fraction of deposited material in plaques compared to pan-Av epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize l-isoaspartate-modified Av (isoD7-Av) and tested a lead antibody molecule in 5xFAD mice. Methods: This work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. Av peptides, containing l-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-Av monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-Av ELISA as well as different non-modified Av ELISA. For antibody treatment studies, 12 mg/kg anti-isoD7-Av antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38 weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze. Results: Our advanced antibody K11 showed a KD in the low nM range and > 400fold selectivity for isoD7-Av compared to other Av variants. By using this antibody, we demonstrated that formation of isoD7-Av may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged Av from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for ...
    Keywords mouse model ; Alzheimer's disease ; Amyloid beta ; isoaspartate ; passive immunotherapy ; Bibliographie ; 610 ; 620
    Subject code 616
    Language English
    Publishing country de
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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