Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid beta plaques and neurofibrillary tangles, along with cognitive impairments that progress to dementia and eventually death. The development of drug treatments that rescue memory deficits could be a promising therapy given in the early stages of AD. In the following studies, we tested the potential for systemic treatment with histone deacetylase (HDAC) inhibitors to ameliorate cognitive deficits in a mouse model of AD. Using the APPSwe/PS1dE9 mouse model of AD, we showed that giving HDAC inhibitors systemically for 3 weeks reversed contextual memory deficits, stably maintained memories over a 2-week period, and targeted Class I HDAC proteins. Additionally, we found that the APPSwe/PS1dE9 memory deficit was not due to a deficit in hippocampal long-term potentiation (LTP), but these mice did show reduction in hippocampal CA1 pyramidal spine density that was restored using an HDAC inhibitor. Finally, we tested the ability of an isoform-selective HDAC inhibitor for HDAC3 and found that it had no effect on restoring APPSwe/PS1ΔE9 contextual memory deficits, indicating that HDAC3 does not play a significant role in the formation of hippocampal-dependent long-term memory.
|Advisor:||Sweatt, John D.|
|Commitee:||Hablitz, John, Roberson, Erik, Rumbaugh, Gavin, Wyss, John M.|
|School:||The University of Alabama at Birmingham|
|School Location:||United States -- Alabama|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Keywords:||Alzheimer's disease, Epigenetics, Hdac inhibitors, Histone deacetylase inhibitors, Learning and memory, Memory dysfunction|
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