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2023 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Mechanisms of Gamma-Secretase Modulators, Towards Rational Drug Design

Can molecules that alter how beta-amyloid is produced in the brain help prevent dementia-related brain changes?

Lucía Chávez-Gutiérrez, Ph.D.
Flanders Institute for Biotechnology, VIB
Gent, Belgium


Beta-amyloid is a protein fragment that accumulates into plaques, one of the hallmark brain changes observed in Alzheimer’s. This fragment is produced from its “parent” molecule, amyloid precursor protein (APP). One of the proteins that cuts beta-amyloid from APP is called gamma-secretase. Gamma-secretase contains four components, the most important being the presenilin components: presenilin-1 (PS1) and presenilin-2 (PS2). Variations in PS1 and PS2 have been linked to Alzheimer’s, especially the rare, inherited form of the disease. Gamma-secretase, however, also carries out other functions vital to brain health, and experimental Alzheimer’s treatments blocking gamma-secretase activity have produced harmful side effects in clinical trials. To develop safer, more effective gamma-secretase treatments, scientists will need to learn more about how this protein promotes amyloid-related changes in dementia.  

In initial studies, Dr. Lucia Chávez-Gutiérrez and colleagues found that presenilin variations alter the cutting of APP in ways that lead to longer beta-amyloid molecules. These longer molecules, including beta-amyloid 42, have been linked to Alzheimer’s and other brain diseases, while the shorter amyloid molecules have been associated with improved brain health. The researchers then identified molecules called gamma secretase modulators (GSMs) could interact with gamma-secretase to produce fewer longer-length amyloid fragments and more shorter-length fragments. 

Research Plan

Dr. Chávez-Gutiérrez and team will work  to clarify how GSMs prevent the development of dementia-related beta-amyloid molecules. First, using gamma-secretase and beta-amyloid molecules grown in a laboratory, they will introduce various GSMs and study how the three molecules bind together. This work will involve identifying the specific areas on the proteins where binding takes place (known as binding sites). It will also enable the researchers to select particular GSMs that may best prevent gamma secreatase from clipping of longer-length beta-amyloid fragments. Next, using the selected GSMs, they will more thoroughly characterize how the molecules interact with gamma-secretase to clip APP and produce beta-amyloid. Lastly, the team will conduct experiments with brain cells grown in a laboratory dish that express gamma-secretase with and without Alzheimer’s-related presenilin variations. The investigators will test how the selected GSMs change how APP is processed in the different cells, and identify whether they can impact the kinds of beta-amyloid produced by gamma-secretase variations. The team will also examine how the GSMs impact other types of gamma secretase activity in the cells.   


Results from this project could shed new light on the role of gamma-secretase in amyloid-related diseases. They could also lead to novel GSM therapies for preventing or slowing Alzheimer’s progression.

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