Session Title: Alzheimer's Disease (AD) including Non-Cognitive Aspects
Presentation Date: Friday, March 14 – Saturday, March 15, 2009
EPIGENETIC CHANGES DURING THE PATHOGENESIS OF ALZHEIMER'S DISAEASE
F. Sananbenesi, R. Agis Balboa, G. Nambirajan, A. Fischer
European Neuroscience Institute, Laboratory for Aging and Cognitive Diseases, Goettingen, Germany
A number of recent studies (Fischer et al, 2007, Nature, 447; Alarcon et al., 2004, Neuron, 42) suggest that epigenetic factors may play a central role in age related pathologies, including Alzheimer's disease (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). We tested the hypothesis 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. We found distinct changes in hippocampal and cortical histone-acetylation of brains for APP transgenic mice and in post-mortem material from human AD patients. The defect in histone-acetylation could be reversed via administration of HDAC inhibitors, which improved cognitive function in APP transgenic mice that suffered from severe amyloid pathology and cognitive impairment. This preliminary data further strengthens the view that targeting epigenetic mechanisms might be suitable to treat cognitive impairment related to AD pathology.