| dc.contributor.advisor | Bayer, Thomas A. Prof. Dr. | |
| dc.contributor.author | Dietrich, Katharina | |
| dc.date.accessioned | 2015-01-14T08:32:13Z | |
| dc.date.available | 2015-01-14T08:32:13Z | |
| dc.date.issued | 2015-01-14 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-9983-3 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4863 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Impact of N-terminally truncated Aß4-42 on memory and synaptic plasticity - Tg4-42 a new mouse model of Alzheimer's disease | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Bayer, Thomas A. Prof. Dr. | |
| dc.date.examination | 2014-12-17 | |
| dc.description.abstracteng | A heterogeneous mixture of amyloid beta (Aβ) variants exists in Alzheimer’s disease (AD) brains. So far, little is known how individual Aβ species contribute to development and progression of this neurodegenerative disorder.
Several studies revealed an important role of N-terminally truncated Aβ species in AD etiology. Besides other Aβ isoforms, N-truncated Aβ4-42 is highly abundant in AD brains and is one of two dominant isoforms in the hippocampus and cortex of sporadic and familial AD subjects. In a recent work it was demonstrated that Aβ4-42 exhibits one of the highest aggregation propensities to form stable aggregates. Moreover, it demonstrates strong toxic effects when studied in primary cortical neurons and is able to induce working memory deficits after intracerebroventricular injection into wildtype mouse brains. Despite these findings a possible role of Aβ4-42 in AD etiology has not been analyzed in detail so far.
The aim of the present work was to investigate the potential neurotoxic effects of Aβ4-42 in in vivo and in vitro model systems. Recently, the first transgenic mouse model expressing exclusively N-terminal truncated Aβ4-42 (Tg4-42 mouse line) was generated in our lab. This mouse model was used to study the effects of Aβ4-42 expression on neuropathology such as Aβ accumulation, inflammation and neuron loss. Furthermore, hemizygous Tg4-42 mice at three and 12 months of age underwent several behavioral tests to assess motor abilities and cognitive function. Acute hippocampal tissue slices of Tg4-42 mice at three, 12 and 24 months of age were used to examine the impact of Aβ4-42 on synaptic function and plasticity. Relative gene expression levels of synaptic markers were additionally analyzed in hippocampal tissue of young Tg4-42 mice.
Using immunohistochemistry, it was shown that Tg4-42 mice develop region-specific intraneuronal Aβ accumulation most notably in the hippocampus starting at two to three months of age. This is accompanied by a marked astro- and microgliosis in the same brain region. DAPI-staining revealed a distinct loss of neuronal cells in hippocampal CA1 area that deteriorates while aging. Additionally, Tg4-42 mice demonstrated age-dependent deficits in spatial learning, spatial reference memory and forms of associative memory when performing Morris water maze and fear conditioning tasks. Neurophysiological analyses in acute hippocampal tissue slices revealed an increased basal synaptic transmission at Schaffer collateral/CA1 synapses. In contrast, short-term and long-term plasticity were not affected. Commencing analysis of gene expression levels demonstrated a down-regulation of synaptoporin and neuroligin 1 levels in hippocampal tissue of three-month-old transgenic mice that might be linked to the detected hyperexcitability. These findings indicate a pathological role for N-truncated
Aβ4-42 in AD etiology as these impairments are comparable to AD typical dysfunctions. | de |
| dc.contributor.coReferee | Hanisch, Uwe-Karsten Prof. Dr. | |
| dc.subject.eng | Alzheimer's disease | de |
| dc.subject.eng | Amyloid-beta | de |
| dc.subject.eng | N-truncated abeta | de |
| dc.subject.eng | Transgenic mouse model | de |
| dc.subject.eng | Tg4-42 | de |
| dc.subject.eng | Morris water maze | de |
| dc.subject.eng | Fear conditioning | de |
| dc.subject.eng | Spatial reference memory | de |
| dc.subject.eng | Associative memory | de |
| dc.subject.eng | Neuron loss | de |
| dc.subject.eng | Synaptic transmission | de |
| dc.subject.eng | Synaptic plasticity | de |
| dc.subject.eng | Long-term potentiation (LTP) | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-9983-3-3 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Medizin (PPN619874732) | |
| dc.identifier.ppn | 815380267 | |