Assessment of Epigenetic profile in Alzheimer's disease

Assessment of Epigenetic profile in Alzheimer's disease

Hope Yao Agbemenyah

Doctoral thesis

Date of Examination: 2012-11-23

Date of issue: 2012-11-30

Advisor: Fischer, André Prof. Dr.

Referee: Nave, Klaus-Armin Prof. Dr.

Referee: Stegmüller, Judith Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-000D-F0C9-9

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Abstract

English

Alzheimer's disease is caused by multivariate factors with a convergent insult to neuronal integrity leading to cognitive decline and neurodegeneration. To develop an efficient therapeutic strategy for treatment of AD calls for a deeper understanding of the biochemical mechanisms that leads to neuronal dysfunction and death. Our data presented here showed that epigenetic factors are involved in AD. They underlie the inception and progression of the disease. We found altered histone acetylation in 4 month old APPPS1-21 mice with a corresponding mild cognitive impairment in the form of spatial memory. A correlation in gene expression i.e. decreased expression of Prkcd, in ac-H4K12 dependent manner was observed. The study also showed that reduced ac-H4K12 was due to increased activity of Hdacs in APPPS1-21 mice and the underlying cause was due to altered enzymatic activity in Sphk2 levels in APPPS1-21 mice. In the other part of our work, we found compromised methylation status in both AD and APPPS1-21 mice which led to elevated levels of IGFBP7 in both conditions compared to controls. Mimicking elevated levels IGFBP7 led to impaired associative memory with a corresponding decrease in activation of Akt. The study further showed that targeting of IGFBP7 reinstated associative memory in 6 month old APPPS1-21 mice. Therefore we propose IGFBP7 could be a potential drug target for therapy in Alzheimer’s disease. The study also showed that AD occurs in a temporal manner in the mouse model of the disease thus suggesting an early diagnosis. In a nutshell epigenetic mechanisms are affected in AD and therapy in the form of specific targeting of modifiers of this process could be advantageous for the treatment of the disease.