A number of studies have shown that the sex hormone, estrogen, has favorable or ?neurotrophic? effects on neuronal cells in the brain. Unfortunately, clinical trials using estrogen revealed unacceptable side effects, including increased risk of blood clots and hormone- sensitive cancers. Moreover, estrogen is not practical for use in men, because it promotes unwanted physical changes and feminizing effects; consequently, estrogen has been abandoned as a treatment for AD. As an alterative strategy, the current study will test a novel drug called ?STX?, which has the favorable neurotrophic effects of estrogen without its unwanted side effects. Preliminary studies indicate that STX protects neuronal cells against Alzheimer?s-associated toxic responses and can be safely given to mice as they age. The overall goal is to determine if STX has potential for treating Alzheimer?s disease in human patients. This drug will be tested first on brain neuronal cells grown in a dish under conditions that mimic specific aspects of Alzheimer?s disease, with the goal of identifying the molecular pathways that control its protective responses. The drug will then will be tested in normal aging mice (to confirm its safety), and in mice that have been genetically engineered to develop Alzheimer-type changes in the brain. Established protocols will be used to carefully assess the effects of STX on memory function, neuronal damage, and brain lesions associated with Alzheimer? Disease. These studies will integrate behavioral tests of spatial memory, immunohistochemical methods to quantify neuronal damage, and biochemical assays to quantify protein aggregation. Concurrently, the molecular pathways identified in cultured neuronal cells will be validated in the brains of treated animals. Successful completion of these experiments will provide the framework for advancing STX toward clinical trials.

Public Health Relevance

This proposal consists of the laboratory evaluation of a potential treatment for Alzheimer?s disease. The treatment is a novel drug (STX) that has many of the favorable effects of the sex hormone, estrogen, without its adverse effects. This drug will be tested in ?model systems? which have been successfully used in Dr.Quinn?s laboratory to evaluate a series of potential treatments in the past, including anti-inflammatory, antioxidant, and metal-chelating drugs. Experiments will be conducted both in cell culture and in mice that are genetically engineered to express aspects of Alzheimer?s disease. If the results are favorable, Dr. Quinn and colleagues will develop the drug further for human use.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003440-01A2
Application #
9451965
Study Section
Neurobiology D (NURD)
Project Start
2018-04-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239