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Master Project Epigenetic Changes in Alzheimer’s disease
Alzheimer´s disease (AD) is a progressive, neurodegenerative disorder, affecting a large number of individuals around the world. It is a disease not only affecting the patients, but also relatives and close friends. Today, there is no cure for AD, instead the treatment is considered to be more symptomatic. There is evidence that the pathological changes seen in AD patients are ongoing for decades before symptoms become manifest. Therefore, it is of great importance to study early changes to understand when to initiate the treatment to get a curative effect. Since the pathological changes are so widespread in AD, e. g. neurodegeneration, deposition of the amyloid-beta (Abeta) peptide, neurofibrillary tangles and inflammatory processes, it is a great challenge to find a treatment that affects all aspects of the disease. An excess of is Abeta postulated to be among the underlying pathological causes of AD. This peptide fragment aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function, eventually leading to neuronal degeneration and dementia.
The suggested research project is focused on understanding how different forms and species of Abeta affect the epigenetic mechanisms in the brain. We want to understand the early effects of Abeta in the disease process and how it is affecting the the neuronal cells during the disease process. Our working hypothesis is that Abeta interferes with the mechanisms that regulate chromatin structure and gene transcription in areas of the brain important for memory and learning. We would also like to use different drugs to try to reverse the effect of Abeta on chromatine structure. Our overall goal is to use the results we obtain to develop new, effective treatment strategies for AD.
We are using several different models to investigate our hypothesis. We have earlier shown that histone modifications are involved in the formation of long-term memory and that the ERK MAPK regulates the acetylation and phosphorylation in hippocampus. Cell studies have shown that treatment with the ?-secretase inhibitor DAPT causes a reduction in histon H3 acetylation, indicating that Abeta changes the chromatine structure of the cells. We will continue our studies to investigate if this is a cell autonomous response or not. We will also try investigate which genes that are up-regulated and via which signal transduction pathways
In conclusion, these studies will provide important information about how Abeta affects cell signaling and the regulation of transcription in the CNS. By identifying these mechanisms, w hope to be able to construct new treatment strategies in AD.
Are you interested, please contact Christina Unger Lithner email: [email protected], phone: 08-585 83615.
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