Although neurogenesis occurs primarily during development, it is an active process that persists throughout life, and may play a role in normal learning and memory. Decreased levels of neurogenesis occur with age and perhaps in neurodegenerative conditions such as Alzheimer's disease (AD). Therefore, understanding the molecular basis of stem cell division and differentiation within the central nervous system (CNS) deserves thorough investigation. A novel drug discovery paradigm was used to select drug candidates for the treatment of neurodegenerative diseases that is based on efficacy in cell culture models of multiple, age-associated pathologies. This scheme has identified a potent, orally active compound, J147, which facilitates memory in normal rodents, prevents behavioral deficits and synaptic protein loss in AD transgenic mice, and reverses cognitive loss in aged transgenic AD mice. J147 is also neurogenic in mice, in adult rat hippocampal precursor cells in culture, and for human ESC-derived neural precursor cells. In addition, it has the unique ability of inhibiting the division of cells destined to be astrocytes. The overall aim in this study is to identify the type and fate of cells that respond to J147 in the mouse brain and to use this compound to better understand the molecular pathways involved in neurogenesis both in vivo and in cell culture models. Therefore the phenotype of the nerve-like cells made in response to J147 will be characterized both in animals and in a rat hippocampal precursor cell line that can produce either nerve or glia. Because the therapeutic potential of compounds like J147 in AD, it will be asked if J147 can induce neurogenesis in very old mice where other neurogenic compounds fail to act. Importantly, neurogenesis will be reduced by two independent methods and it will be asked if J147 is still able to enhance memory. Finally, a new proteomics approach will be used to identify the molecular signaling pathways responsible for J147-induced cell division and nerve differentiation. Results from this study may lead to a therapeutic application of J147 based upon manipulating neural stem cells to improve CNS health.

Public Health Relevance

It is now generally recognized that new nerve cells continue to be produced in the adult brain, but there are currently very few ways to stimulate that process. We have recently made a very potent compound that can stimulate the production of new neurons in both young and old mice. The goal of this project is to better characterize the types of nerve cells that this compound generates and determine how it works.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS077201-02
Application #
8461542
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$231,600
Indirect Cost
$110,975
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Currais, Antonio; Prior, Marguerite; Dargusch, Richard et al. (2014) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. Aging Cell 13:379-90
Prior, Marguerite; Dargusch, Richard; Ehren, Jennifer L et al. (2013) The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice. Alzheimers Res Ther 5:25