APP-Mediated Mechanical Signaling and its Regulation by Alzheimer's Risk Genes

Demonstrate that APP is under mechanical tension in neurons and test whether Alzheimer’s disease risk genes disrupt this force-sensitive signaling pathway.

Our preliminary data revealed for the first time that APP is connected to the force-generation machinery via its interaction with a protein called talin. When combined with the known capacity of APP molecules to interact with each other, this immediately indicated a new role for APP as a tension-bearing linkage and mechanical sensor, where APP cleavage in healthy brains may act as a signal to maintain synaptic health. This provides a big hypothesis for a mechanical basis of Alzheimer’s disease, where disruption of neuronal mechanics contributes to the mis-processing of APP.

If we can prove that APP is a force-bearing molecule and under tension, this will transform the field of Alzheimer’s Disease as we will show a role for APP that is novel, and identify a new cause of the disease. The mechanical signaling machinery that would be maintaining this linkage is well studied in diseases like cancer. We predict that this study will validate a new therapeutic approach for treating Alzheimer’s by targeting neuronal mechanics to slow the spread, and there are a wide range of drugs already on the market for treating cellular mechanics in other diseases.

If we can prove that APP is a force-bearing molecule and under tension, this will transform the field of Alzheimer’s Disease as we will show a role for APP that is novel, and identify a new cause of the disease. The mechanical signaling machinery that would be maintaining this linkage is well studied in diseases like cancer. We predict that this study will validate a new therapeutic approach for treating Alzheimer’s by targeting neuronal mechanics to slow the spread, and there are a wide range of drugs already on the market for treating cellular mechanics in other diseases.