Summary
This project investigates how peripheral immune-metabolic effects, specifically targeting PGE2 signaling, can reverse cognitive decline in aging and Alzheimer's disease models by influencing the blood-brain barrier, astrocytes, and neuronal function.
What they want
The project aims to define how metabolically reprogrammed myeloid cells in the periphery can elicit effects beyond the blood-brain barrier (BBB) that reverse changes in hippocampal function in models of aging and AD pathology. It will test the hypothesis that beneficial immune-metabolic effects of EP2 inhibition on myeloid cells in the periphery are transmitted from the blood to the cerebral endothelium and then to astrocytes, leading to improved astrocytic support of neurons. This will involve preclinical models of aging and mutant APP lines, targeted metabolomics, and transcriptomics to understand how improving peripheral myeloid energy metabolism leads to beneficial effects beyond the BBB. The research will test whether peripheral EP2 immune blockade improves endothelial function and subsequently improves astrocytes and their support of neurons, ultimately leading to improved cognitive function.
Deliverables
- Understanding of how metabolically reprogrammed myeloid cells in the periphery elicit effects beyond the BBB
- Data on the transmission of beneficial immune-metabolic effects of EP2 inhibition from blood to cerebral endothelium and astrocytes
- Insights into how improving peripheral myeloid energy metabolism leads to beneficial effects beyond the BBB
- Evidence regarding whether peripheral EP2 immune blockade improves endothelial function
- Evidence regarding whether astrocytes are functionally improved by peripheral EP2 immune blockade
- Evidence regarding whether peripheral EP2 inhibition improves astrocytic support of neurons and cognitive function
Technical requirements
- Preclinical models of aging and mutant APP lines
- Targeted metabolomics
- Transcriptomics
