Immunometabolic regulation of inflammation in aging and disease
Abstract/Contents
- Abstract
- Alzheimer's disease (AD) is the 6th leading cause of death in the United States and over 43 million people have been diagnosed with AD worldwide. Aging is the number one risk factor for AD, with over 1 in 10 individuals above the age of 65 at risk for developing AD. While it was previously hypothesized that misfolded protein aggregates such as amyloid-beta (Aβ) were sufficient to cause symptomatic AD, more recent research suggests myeloid cells play a fundamental role in the progression of age-associated diseases such as AD. Specifically, circulating pro-inflammatory factors can promote cognitive decline and, in the brain, microglia lose the ability to maintain immune homeostasis and clear misfolded proteins that are associated with neurodegeneration. The molecular mechanisms, however, that initiate and sustain maladaptive inflammation with aging are not well understood. Here, we demonstrate that de novo NAD+ synthesis is active in innate immune cells and is required for maintenance of normal immune homeostasis in inflammation and aging. Specifically, there is a downregulation of quinolinate phosphoribosyl transferase (QPRT), the rate-limiting enzyme for de novo NAD+ synthesis, and replenishment of this enzyme results in rejuvenation of aged myeloid cells. In addition, we demonstrate that the myeloid EP2 receptor in the CNS and periphery converges on a metabolic node of glucose regulation in which glucose is sequestered in aged macrophages, preventing substrate access to the electron transport chain and fuel for oxidative phosphorylation. Coupled with increasing evidence that aged macrophages depend heavily on glucose as a fuel source, these findings reveal a breakdown in energy homeostasis within aging immune cells. Finally, by inhibiting the EP2 receptor in myeloid cells, we are able to restore cognitive function and immune homeostasis in a model of aging.
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 | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Minhas, Paras Singh |
|---|---|
| Degree supervisor | Long, Jonathan |
| Thesis advisor | Long, Jonathan |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Rando, Thomas A |
| Thesis advisor | Wang, Xinnan |
| Degree committee member | Mochly-Rosen, Daria |
| Degree committee member | Rando, Thomas A |
| Degree committee member | Wang, Xinnan |
| Associated with | Stanford University, Neurosciences Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Paras S. Minhas. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/pm746tp3994 |
Access conditions
- Copyright
- © 2021 by Paras Singh Minhas
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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