Cycle 1 project 3

Epigenomic imaging of Alzheimer’s disease: Novel strategies to treat Dementia


PhD student: Pooja Rao, India
Home Institute: European Neuroscience Institute Göttingen; Principle Investigator: André Fischer
Host Institute: Neuroscience Center Zürich; Principle Investigator: Isabelle Mansuy

Executive Summary
Deregulation of neuronal processes is known to cause devastating brain disorders such as Alzheimer’s disease (AD), which cause a huge emotional and economical burden to our societies. AD is the most common neurodegenerative disorder and a major reason for cognitive decline and dementia in the elderly. The epidemiological data available for Europe points to more than 7 million people already affected by dementia, a number expected to double by 2025, in parallel with progress in life expectancy. An effective therapy is not yet available and current drugs that mainly target ion-channels (memantine) or acetylcholinesignaling have only limited therapeutic benefit and are symptomatic.

In sporadic neurodegenerative diseases, a substantial amount of neurons is already lost when the patient is diagnosed (1). From a therapeutic point of view it is therefore of utmost importance to identify neuroprotective strategies, but also approaches that induce neurorestauration. A number of studies (2) (3) (4) (5) (6) (7) and most recent data from our laboratories (8) (9) suggest that epigenetic factors may play a central role in age-related pathologies, including AD and that targeting those mechanisms could be a promising therapeutic avenue.

In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling, especially histone-acetyltransferases (HATs) and histone-deacetylases (HDACs). Our hypothesis, which is supported by published and preliminary data, is that age-related abnormal histone regulation via HATs and HDACs could cause neurodegeneration and cognitive dysfunction by modifying several sets of genes implicated in neuronal functioning. Our plan is to combine all levels of the chain to explore and exploit this possibility and to identify epigenetic therapies towards neurodegeneration. More specifically, we propose to
1. assess the epigenetic regulation of AD in animal models and post-mortem human tissue;
2. to investigate the correlates of hippocampal dependent cognitive impairment in already available and novel animal models of AD pathology;
3. to elucidate the molecular mechanisms by which relevant target genes affect synaptic function, network plasticity, learning and memory.

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