| dc.contributor.advisor | Saher, Gesine Dr. | |
| dc.contributor.author | Winchenbach, Jan | |
| dc.date.accessioned | 2019-03-07T09:26:24Z | |
| dc.date.available | 2019-03-07T09:26:24Z | |
| dc.date.issued | 2019-03-07 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E5BD-6 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7274 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7274 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Genetic manipulation of CNS cholesterol metabolism and its effects on cerebral β-amyloidosis | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Saher, Gesine Dr. | |
| dc.date.examination | 2018-04-12 | |
| dc.description.abstracteng | Accumulating evidence implicates cholesterol metabolism in the pathogenesis of
Alzheimer’s disease (AD). However, the underlying mechanisms are not well
understood. In the brain, cholesterol is synthesized locally by different cell types
during development and in adulthood. The current understanding is that astrocytes
are likely the major producers of cholesterol in the adult brain. However, in vivo
evidence has been limited by the lack of genetic tools that allow efficient targeting
of gene function in adult astrocytes. In this study, a newly generated BAC transgenic
mouse line that expresses tamoxifen inducible Cre recombinase under control of
the Aldh1l1 promoter was characterized. Analyses revealed that astrocytes in brain
and spinal cord are targeted with high efficiency. Using this mouse line we
inactivated cholesterol synthesis in adult astrocytes by targeting of squalene
synthase (SQS), the enzyme catalyzing the first committed step in cholesterol
biosynthesis. Conditional mutants did not show signs of brain pathology and mutant
astrocytes were viable. Interestingly, albeit successful inactivation of SQS in
astrocytes, brain cholesterol homeostasis was largely unaltered, suggesting
compensatory efforts by other cell types. To address the role of astrocytic
cholesterol synthesis in cerebral β-amyloidosis, we crossed conditional mutants with
5xFAD mice, an animal model of AD. In the hippocampus of these compound
mutants, we found reduced deposition of Aβ42 peptides accompanied by increased
expression of Trem2 (triggering receptor expressed on myeloid cells 2). Although
further investigation is required, Trem2 could potentially facilitate Aβ clearance by
microglia cells in these mutants. Together, this study indicates that astrocytic
cholesterol synthesis is not required in adult mice and underlines the importance of
cholesterol metabolism in modulating cerebral β-amyloidosis. | de |
| dc.contributor.coReferee | Bayer, Thomas A. Prof. Dr. | |
| dc.subject.eng | Alzheimer's disease | de |
| dc.subject.eng | Cholesterol | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E5BD-6-6 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1673518885 | |