Testing Candidate Therapies Targeting Dysfunction of Support Cells in Alzheimer's Disease

In this project, researchers will assess how disease-related amyloid-beta affects brain support cell function in Alzheimer’s disease.

Astrocytes are star-shaped brain cells that support neurons in several ways. They are increasingly a focus of research for their potential role in the development of Alzheimer’s disease. For this project, Maria Virtudes Sanchez Mico, PhD, and her colleagues will assess whether disease-related amyloid-beta buildup tracks with increasing dysfunction of astrocytes.

The team will leverage fluorescent molecular biology tools to follow the trajectory of dysfunction in astrocytes in relation to how they metabolize specific molecules. Using these newly developed fluorescent biosensors, Dr. Sanchez Mico and coworkers will follow these processes in real time while also tracking amyloid-beta accumulation simultaneously in lab models. The researchers predict that astrocyte dysfunction will intensify with amyloid-beta buildup.

With these powerful, sophisticated tools, Dr. Sanchez Mico and her colleagues will then assess how two candidate treatments fare in restoring proper astrocyte function. Because the researchers will be following these processes in real time in lab models, they will have a window on how these interactions evolve from their start in the living brain. The results are expected to highlight potential early targets for treatments in Alzheimer’s disease.

The final postmortem AD diagnosis is limited since it does not permit longitudinal monitoring of the pathology. For this reason, monitoring the evolution of specific metabolic and signaling dynamics of astrocytes in vivo over the course of the disease will allow us to understand the mechanisms whereby Abeta causes this dysfunction. In vivo multiphoton microscopy and newly developed fluorescent biosensors are powerful, advantageous tools for this purpose. We are uniquely qualified to perform these experiments with our vast experience in using fluorescent probes and imaging in vivo.

Our study has two foreseeable benefits to the public. First, it will allow us to more clearly understand how Abeta alters the normal function of astrocytes in vivo, and thus increase our understanding of Alzheimer’s pathophysiology and establish future mechanistic studies. Second, our experiments will determine the effect of two promising therapeutic approaches in astroglial redox metabolism in vivo, with the final objective of facilitating the development of therapeutic strategies to prevent/retard the progression of this devastating disease.