Early Aβ-targeting interventions in mouse models of Alzheimer pathology

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dc.contributor.advisor Jucker, Mathias (Prof. Dr.)
dc.contributor.author Uhlmann, Ruth Elisabeth
dc.date.accessioned 2020-05-05T14:21:22Z
dc.date.available 2020-05-05T14:21:22Z
dc.date.issued 2022-03-31
dc.identifier.uri http://hdl.handle.net/10900/100258
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1002581 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-41639
dc.description.abstract Alzheimer’s disease (AD) is the leading form of dementia affecting approximately 35 million people worldwide. So far, only symptomatic treatment is approved which does not change the course of the disease. Over the last years, prevention trials for AD started to rise new hope for effective therapies based on the knowledge that changes in amyloid-β (Aβ) levels can be detected more than two decades before symptom onset. However, the most beneficial timepoint for early intervention and the best treatment strategies remain unknown. We examined the concepts of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition and anti Aβ immunization as prevention strategies. In the first study of this thesis, the optimal timepoint for intervention during pathogenesis was determined. Amyloid precursor protein (APP) transgenic mice were treated for three months with a potent BACE1 inhibitor at an early, intermediate or late stage of pathology or chronically for either half-lifelong or lifelong duration. Effects on neurodegeneration and associated pathologies were established. In the second study, well described anti-Aβ antibodies were applied to APP transgenic mice at initial stage of β-amyloidosis. Their ability to neutralize seeding-active Aβ assemblies was investigated in order to assess preventive effects at sub-threshold Aβ levels before Aβ increase can be detected. Furthermore, antibody recognition profiles using size-fractionated brain-derived Aβ assemblies were established. In the first study, early BACE1 inhibition robustly reduced Aβ deposition and halted neurodegeneration, whereas at later stages of pathology, neurodegeneration became uncoupled of β-amyloidosis. In the second study, acute immunization with an anti-Aβ antibody led to a long-term significant reduction of Aβ deposition and downstream pathologies, demonstrating the presence of pathogenic Aβ seeds before Aβ deposition can be detected. Findings imply that preclinical therapy should shift to initial stages of Aβ dyshomeostasis before β-amyloid deposition is detectable. This primary prevention approach may forestall further seed formation and neurodegeneration, thereby preventing the onset of AD. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podno de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=en en
dc.subject.classification Alzheimerkrankheit de_DE
dc.subject.ddc 500 de_DE
dc.subject.other Alzheimer's disease en
dc.subject.other Intervention en
dc.subject.other Immunization en
dc.title Early Aβ-targeting interventions in mouse models of Alzheimer pathology en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2020-04-23
utue.publikation.fachbereich Graduiertenkollegs de_DE
utue.publikation.fakultaet 8 Zentrale, interfakultäre und fakultätsübergreifende Einrichtungen de_DE
utue.publikation.noppn yes de_DE


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