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In Vitro and In Vivo Studies on Antibodies - N-terminally Truncated Abeta in the 5XFAD Mouse Model

dc.contributor.advisorBayer, Thomas A. Prof. Dr.
dc.contributor.authorRichard, Bernhard Clemens
dc.titleIn Vitro and In Vivo Studies on Antibodies - N-terminally Truncated Abeta in the 5XFAD Mouse Modelde
dc.contributor.refereeBayer, Thomas A. Prof. Dr.
dc.description.abstractengCommonly used transgenic mouse models mimic Alzheimer´s disease (AD) to some extent but do as well display differences compared to the human AD phenotype. Growing evidence indicates that N-terminally truncated isoforms, which are underrepresented in common murine models, represent a key player in AD. These peptides are abundant in AD brains and have increasingly gained attention during the past years. It has been suggested that the equilibrium of aggregation is shifted towards the more toxic low-molecular weight oligomeric assemblies due to N-terminal truncation of Aβ, thereby triggering neurodegenerative processes. In this study, characterization of a recently developed monoclonal antibody, NT4X-167, revealed its engagement with N-terminally truncated AβpE3-x and Aβ4-x. We also showed the propensity of Aβ4-x to adopt a distinct oligomeric conformation. Analysis of a newly created homozygous 5XFAD mouse strain with NT4X-167 revealed early intracellular accumulation of Aβ4-x in this model, preceding other N-truncated isoforms, AβpE3-x and Aβ5-x. Investigation of homozygous 5XFAD mice revealed a gene-dose dependence of the neuropathological and behavioral phenotype. Homozygous 5XFAD might especially facilitate the analysis of intracellular Aβ, truncated isoforms in particular. Considering the consensus that Aβ is a key player on one hand, and the failure of recent anti-Aβimmunotherapeutic trials in AD on the other hand, there is an urgent need to find new therapeutic targets and strategies. In the course of this, it has been proposed that targeting N-truncated Aβ might offer therapeutic advantage. In order to explore the therapeutic potential of passive anti-N-truncated Aβ immunization, a comparative study with three monoclonal antibodies (NT4X-167, 9D5, 1-57) in 5XFAD was conducted in this study. As NT4X-167 showed a significant effect, it can be concluded that this antibody might offer therapeutic advantage over antibodies specific for Aβ
dc.contributor.coRefereeOuteiro, Tiago Fleming Prof. Dr.
dc.subject.engAlzheimer´s Diseasede
dc.subject.engpassive Immunizationde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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