Jawhar, Sadim

English

AD 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 AD

Georg-August-University Göttingen

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

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-0006-B5D8-7/1/jawhar.pdf

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

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Georg-August-University Göttingen