Alzheimer's disease (AD) is the most common human neurodegenerative disorder of the CNS and one of the most common signs of AD is memory loss. Despite intense investigations, no effective therapy is available to improve memory in AD. Peroxisome proliferator-activated receptor (PPAR) ? is a transcription factor that regulates genes involved in fatty acid catabolism. Although hippocampus does not metabolize fat, recently we have demonstrated that PPAR? is constitutively expressed in nuclei of hippocampal neurons and surprisingly controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of CREB. Being a nuclear hormone receptor, PPAR? needs ligand(s) for translocation into the nucleus. Because PPAR? is constitutively present in nuclei of hippocampal neurons, ligands must be constitutively present in the hippocampal neurons as well. Interestingly, we have identified three novel ligands (Hexadecanamide, Octadecenamide and 3-hydroxy, 2, 2-dimethyl butyrate) from hippocampal extracts of normal mice. Here, we would like to examine functions of these novel ligands in the hippocampus, compare levels of these ligands and their receptor PPAR? in the hippocampus of patients with AD, mild cognitive impairment (MCI) and age-matched controls with no cognitive impairment, and delineate whether these ligands improve memory and learning in an animal model of AD via PPAR?. A positive outcome of this grant proposal will highlight the discovery of novel hippocampal ligands of PPAR?, allowing us to develop hippocampus-based drugs to enhance synaptic plasticity and protect memory and learning in cognitive disorders including AD.

Public Health Relevance

Despite intense investigations, no effective therapy is available to improve memory in patients with Alzheimer's disease (AD). We have identified three novel ligands of PPAR? from the hippocampus and here, we would like to examine functions of these novel ligands in the hippocampus and delineate whether these ligands improve memory and learning in an animal model of AD via PPAR?. A positive outcome of this grant proposal may highlight the discovery of novel hippocampus-based drugs to enhance synaptic plasticity and protect memory and learning in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG050431-03
Application #
9514780
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Refolo, Lorenzo
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
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