| dc.contributor.advisor | Wirths, Oliver PD Dr. | |
| dc.contributor.author | Hüttenrauch, Melanie | |
| dc.date.accessioned | 2016-06-01T10:01:35Z | |
| dc.date.available | 2016-06-01T10:01:35Z | |
| dc.date.issued | 2016-06-01 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0028-8767-C | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5666 | |
| dc.language.iso | deu | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Alzheimer-like pathology in murine transgenic models: disease modification by environmental and genetic interventions | de |
| dc.type | doctoralThesis | de |
| dc.title.translated | Alzheimer-like pathology in murine transgenic models: disease modification by environmental and genetic interventions | de |
| dc.contributor.referee | Wirths, Oliver PD Dr. | |
| dc.date.examination | 2016-05-18 | |
| dc.description.abstracteng | As no successful therapeutic approach to treat Alzheimer’s disease (AD) has been developed to date, preventative strategies and non-pharmacological interventions increasingly become a major research focus. In recent years, substantial evidence for a protective role of physical and cognitive activity on the risk of AD has been growing. In the present study, the effect of a challenging environment in combination with regular exercise on the Alzheimer-like pathology of the Tg4-42 and 5XFAD mouse models was investigated.
The Tg4-42 model overexpresses N-truncated Aβ4-42 without any mutations and develops an age- and dose-dependent neuron loss in the CA1 region of the hippocampus associated with a severe memory decline. It could be shown that long-term cognitive and physical stimulation significantly delay hippocampal neuron loss and completely rescue memory deficits in 12-month-old Tg4-42 mice. Moreover, long-term gene expression profile changes yielding to neuroprotective events could be observed in enriched housed Tg4-42 mice. These effects were irrespective of brain Aβ4-42 levels and increased neurogenesis rates. The present findings provide evidence for the first time that neuron loss and memory decline can be counteracted by prolonged physical and cognitive activity in a mouse model that rather reflects the sporadic form of AD.
The 5XFAD model is a well-characterized, commonly used AD model for the familial form of the disease, representing an early and aggressive pathology. In the present work, it could be demonstrated that prolonged cognitive and physical activity has no therapeutic benefit on the pathophysiology of this conventional 5XFAD model. Despite partial improvements in motor performance, no beneficial effects in terms of behavioural deficits, Aβ plaque deposition, Aβ1-42 levels or inflammatory phenotype were observed. These results suggest that a rather mild intervention like mental stimulation and regular exercise cannot counteract the aggressive AD pathology seen in 5XFAD mice.
In sporadic AD cases, a decelerated degradation of Aβ is supposed to be the primary cause of an enhanced accumulation of the peptide in the brain. Neprilysin (NEP) represents the major Aβ-degrading enzyme as shown by numerous in vitro and in vivo studies and hence is assumed to play a pivotal role in the progression of AD. In order to gain deeper knowledge about the function of NEP, 5XFAD mice were crossed with homozygous NEP knock-out mice. NEP reduction led to an impaired spatial working memory performance in 6-month-old 5XFAD mice. Furthermore, depletion of the enzyme increased extracellular amyloid deposition in specific brain regions and enhanced the inflammatory response in the brain. In young 5XFAD mice, however, NEP knock-out led to a delayed Aβ plaque deposition accompanied by elevated levels of the NEP homologue endothelin-converting enzyme 1 (ECE1). These data support previous observations showing that NEP is a substantial Aβ-degrading enzyme and suggest a reciprocal effect between NEP and ECE1 activities in young 5XFAD mice. | de |
| dc.contributor.coReferee | Outeiro, Tiago Fleming Prof. Dr. | |
| dc.subject.eng | Alzheimer's disease | de |
| dc.subject.eng | Physical and cognitive activity | de |
| dc.subject.eng | Environmental enrichment | de |
| dc.subject.eng | Tg4-42 mouse model | de |
| dc.subject.eng | 5XFAD mouse model | de |
| dc.subject.eng | Hippocampal neuron loss | de |
| dc.subject.eng | Neurodegeneration | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8767-C-9 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 860281078 | |