Ashley I. Bush, M.D., Ph.D.
Mental Health Research Institute of Victoria
Parkville, Australia

2007 Investigator-Initiated Research Grant

Beta-amyloid is a protein fragment suspected of disrupting cell-to-cell communication and damaging cells in Alzheimer’s disease. Beta-amyloid clumps together in stages, eventually forming amyloid plaques in a process called aggregation. However, clusters of only a few protein fragments in early stages of aggregation may be the most toxic forms of beta-amyloid. These forms are called oligomers.

A major effort of Alzheimer research is to develop drugs that can reduce brain beta-amyloid levels by altering how the brain processes the protein fragment. Studies have shown that beta-amyloid is inclined to interact with copper and zinc ions, and this interaction may affect how rapidly oligomers and other aggregates form.

Ashley I. Bush, M.D., Ph.D., and colleagues have been trying to identify molecules that destabilize amyloid aggregates.  These molecules would bind to the zinc and copper in those plaques. Such destabilization may enable the brain to clear out beta-amyloid. Recently, Dr. Bush’s team developed a compound called PBT2 that has shown promising results with mice geneti-cally engineered to develop Alzheimer-like symptoms. PBT2 has both reduced beta-amyloid levels and reversed cognitive impairment in the mice.

For this grant, Dr. Bush’s group will conduct a more thorough study of PBT2 with their mice. Results could lead to the development of drugs that reduce both the pathological and symptomatic progression of Alzheimer’s disease.