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2022 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Strategies Disrupting the Feed-Forward Mechanism of Aß Production.

How can the production of disease-related brain changes be prevented?

Elena Anahi Bignante, Ph.D.
Instituto de Investigación Médica Mercedes y Martín Ferreyra
Cordoba, Argentina


In Alzheimer’s, the proteins beta-amyloid and tau accumulate to form plaques and tangles respectively, two hallmark brain changes observed in the disease. Beta-amyloid plaques may hinder nerve cell communication in the brain and may contribute to brain cell death. Beta-amyloid is produced from amyloid precursor protein (APP), in a two-stage process. The first stage involves an enzyme (or cutting protein) called beta-secretase 1 (BACE1).

In initial studies with brain cells in a laboratory dish, Dr. Elena Bignante and colleagues found that when small beta-amyloid clumps called oligomers were added to the cells, APP and BACE1 molecules tended to accumulate together in certain brain cell compartments. Their finding suggests that beta-amyloid oligomers may initiate specific biology that act as a “feed-forward” mechanism. These changes may activate a chemical process that eventually leads to the production of still more beta-amyloid. This feed-forward mechanism may eventually promote plaques and the brain damage associated with those plaques.

Research Plan

Dr. Bignante and team will conduct a study to verify and expand on their and others’ earlier findings. First, they will analyze in more detail how amyloid oligomers impact interaction of APP and BACE1. Using specific cellular models of disease, the investigators will determine whether a particular signaling pathway (or series of chemical events in the cell) is involved in carrying out the oligomers’ feed-forward process. Using genetically engineered Alzheimer’s-like mice, Dr. Bignante’s team will also determine whether increasing the activity of certain molecules in the mice brains can impact these signaling pathways.  They will also determine if there are other changes linked to Alzheimer’s that also take place by increasing activity of these molecules, including the spread of abnormal tau protein and changes in learning and memory. 


Results from Dr. Bignante’s study could shed new light on disease-related brain changes. They could also lead to novel therapeutic targets for Alzheimer’s.

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