Vitamin B12 impacts amyloid-β induced proteotoxicity by regulating the methionine/s-adenosylmethionine cycle
| Author(s) | Lam, Andy B. | |
| Date Accessioned | 2022-10-14T13:52:39Z | |
| Date Available | 2022-10-14T13:52:39Z | |
| Publication Date | 2022 | |
| SWORD Update | 2022-08-10T19:08:24Z | |
| Abstract | Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, the complexity of the human diet and the indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis including amyloid-beta (Aβ) deposition, energy crisis, and oxidative stress. Here I used a transgenic Aβ expressing Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity. Caenorhabditis elegans are free-living, non-parasitic nematodes that can be maintained in laboratory settings with E. coli OP50 or E. coli HB101 used for food. I discovered nematodes raised on HB101 experienced a delay in Aβ-induced paralysis. This delay in paralysis was not due to caloric restriction or changes in Aβ accumulation. The HB101 diet also protected against Aβ-induced reduction in ATP levels, increased mitochondrial fragmentation, and increased reactive oxygen species levels. OP50 and HB101 E. coli have varying levels of carbohydrate content and fatty acid composition, which can elicit different physiological effects in C. elegans However, these differences in macronutrients do not underlie the protective effects of HB101 as supplementation with either glucose or oleic acid failed to eliminate the dietary shift. Instead, I discovered that the protective effect of HB101 was due to the availability of vitamin B12. Vitamin B12 supplementation delayed Aβ-induced paralysis and protected against energy defects in animals raised on OP50, a B12 deficient E. coli, but had no additive effects for Aβ animals fed HB101. Interestingly, a decrease in B12 availability during adulthood exacerbated Aβ proteotoxicity, while increasing B12 availability in adulthood was protective. These results suggest that the protective effects of B12 depend on pre-existing B12 status. I next determined that the protective effects of vitamin B12 were due to its function as a cofactor for methionine synthase, as loss of methionine synthase (metr-1) and SAMe synthase (sams-1) eliminated the dietary shift. Increased methionine/S-adenosylmethionine (SAMe) cycle activity can increase the synthesis of membrane phosphatidylcholine (PtdCho) through SAMe dependent methylation of phosphoethanolamine. Supplementation with either choline or PtdCho delayed Aβ-induced paralysis. Together, these results suggest a model in which vitamin B12 dependent methionine/SAMe cycle activity increases phosphatidylcholine production to reduce Aβ proteotoxic effects. Future experiments will focus on validating this model by evaluating phosphatidylcholine levels and determining how changes in membrane phospholipid composition impact amyloid-beta induced proteotoxicity | en_US |
| Advisor | Tanis, Jessica E. | |
| Degree | Ph.D. | |
| Department | University of Delaware, Department of Biological Sciences | |
| DOI | https://doi.org/10.58088/g253-ep84 | |
| Unique Identifier | 1347441734 | |
| URL | https://udspace.udel.edu/handle/19716/31482 | |
| Language | en | |
| Publisher | University of Delaware | en_US |
| URI | https://login.udel.idm.oclc.org/login?url=https://www.proquest.com/dissertations-theses/vitamin-b-sub-12-impacts-amyloid-β-induced/docview/2700747679/se-2?accountid=10457 | |
| Keywords | Alzheimer's disease | |
| Keywords | Amyloid-beta | |
| Keywords | C. elegans | |
| Keywords | Methionine | |
| Keywords | S-adenosylmethionine | |
| Keywords | Vitamin B12 | |
| Title | Vitamin B12 impacts amyloid-β induced proteotoxicity by regulating the methionine/s-adenosylmethionine cycle | en_US |
| Type | Thesis | en_US |