Pharmacological interventions that prevent or delay memory loss associated with aging would substantially improve quality of life for affected individuals, increase their productivity, and decrease the health care costs for those with memory loss and dementia. Memory deficits are common to aging and neurodegenerative diseases like Alzheimer’s disease. Because the U.S. population is rapidly aging, the incidence of memory dysfunction will increase exponentially. Although memory dysfunction is a significant impediment to independent living and diminishes workforce productivity, few treatments effectively prevent or reverse memory impairments. An extremely promising avenue for such treatment is the use of histone deacetylase inhibitor drugs (HDACis).
A promising avenue for such treatment is the use of histone deacetylase inhibitor drugs. Dr. Frick and others have found that HDACis increase synaptic plasticity in the brain and enhance learning and memory in mouse models of Alzheimer’s disease1, 2. These findings raise the possibility that HDACis could reduce cognitive impairment in the elderly and patients with neurodegenerative diseases. Small molecule HDACis, such as FK228 and SAHA (Fig 1), have been approved for the treatment of certain cancers, but their effectiveness is limited by unwanted toxicity and/or poor solubility. Dr. Hossain and colleagues have synthesized a small library of potent HDACi molecules that show good solubility and low toxicity in mice (Table 1). Here, we will test the ability of 3 lead compounds to enhance the formation of two types of memory. Thus, the goal of this study is to test the effects of novel, non-toxic HDACi compounds on memory in a well-established mouse model of memory formation with which the PI has extensive experience. These proof-of-principle data are needed to apply for federal and foundation funding to conduct more extensive testing, a patent application, and to eventually attract licensing partners such as Merck or Takeda that are active in Alzheimer’s drug research.
This study is designed to develop and test the effects of novel, non-toxic histone deacetylase inhibitor compounds on memory in order to reduce memory decline in aging and Alzheimer’s disease.