Novel roles for the EP2 receptor in Alzheimer's disease
Abstract/Contents
- Abstract
- Microglia, the primary immune cells of the central nervous system, are critical to the inflammatory homeostasis of the brain. These cells halt toxic inflammation and clear debris, degrading misfolded proteins and clearing plaques. In cases of severe inflammation, aging, or neurodegenerative disease, however, microglia become overwhelmed, and their beneficial functions are replaced by dysfunctional, pro-inflammatory responses, further catalyzing the brain's loss of synapses and neurons. In an effort to bolster microglial clearance and halt this feed-forward pathology, the prostaglandin EP2 receptor was recently established as a key regulator of myeloid dysfunction in mouse models of Alzheimer's disease. My current findings indicate that this EP2 receptor deletion improves myeloid cell function by orchestrating lysosomal and mitochondrial activity. Specifically, deletion of EP2 mobilizes the CLEAR network, a canonical regulator of lysosomal clearance and recently-established regulator of mitochondrial biogenesis and function that I find is broadly implicated in microglial affected by neurological disease. Suppressing EP2 signaling in microglia and macrophages stimulates lysosomal gene expression, biogenesis, and function, rescuing degradative capacity that is otherwise suppressed by amyloid beta (Aβ), a misfolded protein implicated in Alzheimer's disease. Concurrently, EP2 deletion stimulates mitochondrial biogenesis, simultaneously rescuing oxidative phosphorylation and metabolite production, both impaired by Aβ. Together, these findings demonstrate that myeloid EP2 signaling coordinates and orchestrates immunometabolism and lysosomal degradation and, in this way, may serve as a critical target to restore healthy microglial function, prevent neuroinflammation, and stall progression of Alzheimer's disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Rubin, Amanda Joy |
|---|---|
| Degree supervisor | Andreasson, Katrin |
| Degree supervisor | Ricci, Anthony |
| Thesis advisor | Andreasson, Katrin |
| Thesis advisor | Ricci, Anthony |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Reimer, Richard J |
| Thesis advisor | Wang, Xinnan |
| Degree committee member | Palmer, Theo |
| Degree committee member | Reimer, Richard J |
| Degree committee member | Wang, Xinnan |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Amanda Joy Rubin. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Amanda Joy Rubin
Also listed in
Loading usage metrics...