The current thesis investigated a potential relationship between Alzheimer disease
and type-2 diabetes mellitus by analysing early gene expression related to insulin
receptor signalling in the hippocampus as well as glucose metabolism in APP/PS1
mice, a model of familial Alzheimer disease.
Compared to wild-type animals, a reduction in hippocampal insulin receptor and
insulin-receptor substrate 2 transcripts in APP/PS1 mice three-month old as well as
an increase in insulin-like growth factor 2 transcripts after six months was detected
using real-time polymerase chain reaction. The alterations in hippocampal insulin
signalling were accompanied by perturbation of glucose metabolism analysed by
intraperitoneal glucose tolerance test. At the age of six months APP/PS1 mice
developed glucose intolerance.
Learning and recognition memory in APP/PS1 mice were tested using the Novel
Object Recognition Test. Cognitive decline became evident in APP/PS1 mice at six
months of age.
Degradation of both insulin and amyloid β is mediated through insulin-degrading
enzyme. However, expression of insulin-degrading enzyme in APP/PS1 mice was notdifferent from wild-type littermates.
Changes in hippocampal phosphorylation of the tau phosphoepitopes serine 199,
threonine 205, serine 396 and serine 404 were investigated using Western blot.
Levels of three phosphoepitopes were increased significantly at either age.IV
Protein expression of the phosphorylated form of glycogen synthase kinase 3β
remained unchanged indicating an alternative pathway of tau phosphorylation in the
APP/PS1 mouse model of familial Alzheimer disease.
The current results demonstrate an increase in cyclin-dependant kinase 5
phosphoralyted at tyrosine 15 in APP/PS1 mice at three and six months of age. The
correlation between elevated levels of phosphorylated tau and cyclin-dependant
kinase 5 suggests that cyclin-dependant kinase 5 might contribute to tau
phosphorylation in APP/PS1 mice.
In general, this work corroborates common pathologic features in Alzheimer disease
and diabetes mellitus. A significant cognitive decline in APP/PS1 mice was
associated with changes in early gene expression of insulin-related molecules and
perturbations in glucose metabolism. Cyclin-dependant kinase 5 is considered to coregulate tau phosphorylation in APP/PS1 mice, and to be part of a pathway
contributing to pathology in Alzheimer disease
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:17117 |
| Date | 07 February 2018 |
| Creators | Allgaier, Michael |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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