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The 5XFAD mouse model: a tool for genetic modulation of Alzheime's disease pathology

dc.contributor.advisorBayer, Thomas A. Prof.
dc.contributor.authorJawhar, Sadimde
dc.titleThe 5XFAD mouse model: a tool for genetic modulation of Alzheime's disease pathologyde
dc.contributor.refereeBayer, Thomas A. Prof.
dc.subject.dnb500 Naturwissenschaftende
dc.description.abstractengAD mouse models contributed widely to our understanding of the pathophysiology of AD and represent invaluable tools in testing potential therapeutic interventions. In the present study, age-dependent characterization of the neuropathological and behavioral hallmarks of the 5XFAD mouse model was performed, demonstrating that the 5XFAD mouse model develops a variety of AD neuropathological and behavioral hallmarks. It was shown for the first time that the 5XFAD mice develop neurological and motor phenotypes, which coincide with spinal cord pathology such axonopathy and intraneuronal (amyloid beta) Aâ. One of the most important characteristics originally reported in the 5XFAD mouse model is the neuron loss; however, this was never appropriately quantified. Using designed-based stereology, it was shown that the 5XFAD mice develop significant selective neuron loss in the fifth cortical of the frontal cortex which correlates with the accumulation of intraneuronal Aâ peptides. The 5XFAD mouse model develops early age-dependent alterations in anxiety levels and impaired spatial working memory starting from 6 months of age. Employing a variety of Aâ specific antibodies, abundant intraneuronal Aâ and extracellular plaque deposition was noted and showed age-dependent alterations. Altogether, the simultaneous occurrence of age-dependent neuropathological and the behavioral changes present the 5XFAD mouse model as an invaluable model to study AD. More importantly, the cosegregation of the mutations in the 5XFAD facilitates its use to generate bigenic mouse models. pyroglutamate Aâ (AâpE3-x) is a modified form of Aâ which is particularly interesting due to its predominance in AD brains and its high pathogenicity. The above mentioned considerations, in addition to the early deposition and the abundance of AâpE3-x in the 5XFAD mouse model, prompted its use to test genetic strategies for modulating this Aâ isoform. Several in vitro and in vivo lines of evidence suggested that glutaminyl cyclase (QC) enzyme is responsible for the formation of AâpE3-x. In order to study the pathological contribution of QC to the pathology of AD, 5XFAD mice were crossed with hQC mice to generate a bigenic model of AD with QC overexpression, the 5XFAD/hQC model. The 5XFAD/hQC mouse model brought together QC and the Aâ precursor leading to higher AâpE3-x levels. As a consequence, the 5XFAD/hQC mice exhibited higher AâpE3-x plaque pathology and accelerated motor and spatial working memory impairments in comparison to the 5XFAD mice. More importantly, the endogenous contribution of QC to AD pathology was studied by generating the 5XFAD/QC-KO bigenic mouse model. Complete depletion of QC reduced AâpE3-42 and Aâx-42 concentrations, alleviated the plaque pathology and improved the memory impairment in the 5XFAD/QC-KO mouse model. Taken together, the outcome of this work clearly indicates the pivotal role of QC in AD pathology. In summary, the aim of this thesis was to perform an age-dependent characterization of the 5XFAD mouse model and to verify its use in studying strategies that modulate AâpE3-x and thus AD pathology. Based on that, data from the 5XFAD/hQC and the 5XFAD/QC-KO mice clearly demonstrate that QC is an essential enzyme modulating AâpE3-42 levels in vivo and proves on a genetic basis the concept that reduction of QC activity is an interesting new therapeutic approach for
dc.contributor.coRefereeFischer, André Prof.
dc.contributor.thirdRefereeWouters, Fred Prof.
dc.subject.topicGöttingen Graduate School for Neurosciences and Molecular Biosciences (GGNB)de
dc.subject.gerAlzheimer'r disease. Amyloid betade
dc.subject.gerGlutaminyl cyclasede
dc.subject.engAlzheimer'r disease. Amyloid betade
dc.subject.engGlutaminyl cyclasede
dc.subject.bk42.00 Biologie: Allgemeinesde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullWA 000: Biologiede

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