2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)
Structural and mechanistic understanding of gamma-secretase modulation
Can molecules that alter how beta-amyloid is produced in the brain help prevent Alzheimer’s-related brain changes?
Mohamed Belal Hamed Soliman, Ph.D
Vlaams Instituut voor Biotechnologie (Flanders Institute for Biotechnology, VIB)
Gent, Belgium
Background
One of the hallmark brain changes that occurs in Alzheimer’s is the abnormal accumulation of the beta-amyloid to form amyloid plaques. Beta-amyloid is produced from its parent protein by the cutting action of a series of proteins including one known as gamma-secretase. Several compounds that reduces or blocks gamma-secretase activity have been developed as potential drug candidates for Alzheimer’s. However, since gamma-secretase has other important functions within the cell, these compounds have had negative side effects. Several studies are focusing on discovering new compounds called gamma-secretase “modulators” (GSMs) that work by specifically preventing the ability of gamma-secretase to produce toxic beta-amyloid without interfering with its other normal functions.
Research Plan
For their studies, Dr. Mohamed Soliman and colleagues aim to develop new GSMs that can modify gamma-secretase to produce smaller fragments of beta-amyloid that can be cleared by the brain’s waste disposal system, preventing their build-up and amyloid plaque accumulation. First, using gamma-secretase and beta-amyloid molecules grown in a laboratory, they will introduce various GSMs and identify the specific areas where the molecules interact. The researchers will also measure how tightly the molecules physically interact together to identify GSMs that will be less likely to interact with other proteins in the cells and have negative side effects. Lastly, the team will measure the fragment lengths of beta-amyloid that are produced when the molecules interact to identify which GSMs best enable gamma-secretase to cut shorter fragments.
Impact
Results from this study could lead to novel GSM therapies for preventing or slowing Alzheimer’s progression.