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2016 Grants - Zhang
Targeting Appoptosin for Intervention of Alzheimer’s and Other Tauopathies
Yunwu Zhang, Ph.D.
Sanford-Burnham Medical Research Institute
La Jolla, CA
2016 Collaboration 4 Cure (C4C) Grant
Can novel molecules that inhibit high levels of the appoptosin protein protect against nerve cell death in Alzheimer’s?
The accumulation of beta-amyloid into “plaques” and abnormal tau protein into “tangles” are hallmark brain changes associated with Alzheimer’s disease. Abnormal tau also accumulates in several other brain diseases collectively known as tauopathies. While research suggests that build-up of beta-amyloid and tau contributes to nerve cell damage the underlying molecular mechanisms are not yet clear.
Recent studies from Dr.Yunwu Zhang and colleagues have shown that when nerve cells in a laboratory dish are exposed to beta-amyloid, levels of a protein called appoptosin increase. High levels of appoptosin are observed in various dementias and are thought to promote the accumulation of abnormal tau which can contribute to nerve cell damage. Taken together, these observations suggest that preventing an increase in appoptosin levels in nerve cells exposed to beta-amyloid may reduce the formation of abnormal tau and protect against nerve cell death.
Dr. Yunwu Zhang and team have proposed studies to discover drug-like molecules that interfere with the ability of beta-amyloid to increase appoptosin levels. They will use a novel method in which the gene that encodes appoptosin is “connected” to a gene that encodes a fluorescent protein; therefore when the appoptosin gene is turned on by beta-amyloid, a fluorescent signal is detected. Using cells grown in a laboratory dish, the researchers will test over a thousand drug-like molecules to determine which ones are able to turn off the fluorescent signal, indicating their ability to block the activation of appoptosin in response to beta-amyloid. The most promising molecules will then be tested for their ability to protect nerve cells from developing tau protein tangles and undergoing cell death.
These studies may help rapidly identify new drug-like molecules that inhibit high levels of appoptosin in nerve cells. These novel drug candidates can then be further investigated as potential treatments to slow, halt, or prevent Alzheimer’s and other neurodegenerative diseases.