Journal
CELL DEATH & DISEASE
Volume 11, Issue 10, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-020-03020-9
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Funding
- Shiley-Marcos Alzheimer's Disease Research Center at University of California San Diego
- Innovation Award from the Salk Institute
- Paul F. Glenn Center for Biology of Aging Research at the Salk Institute
- Shiley Foundation
- NIH [AG046153, AG054714, AI104034, NS106305]
- NIH-NCI [CCSG: P30 014195]
- Helmsley Trust
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Amyloid beta (A beta) accumulates within neurons in the brains of early stage Alzheimer's disease (AD) patients. However, the mechanism underlying its toxicity remains unclear. Here, a triple omics approach was used to integrate transcriptomic, proteomic, and metabolomic data collected from a nerve cell model of the toxic intracellular aggregation of A beta. It was found that intracellular A beta induces profound changes in the omics landscape of nerve cells that are associated with a pro-inflammatory, metabolic reprogramming that predisposes cells to die via the oxytosis/ferroptosis regulated cell death pathway. Notably, the degenerative process included substantial alterations in glucose metabolism and mitochondrial bioenergetics. Our findings have implications for the understanding of the basic biology of proteotoxicity, aging, and AD as well as for the development of future therapeutic interventions designed to target the oxytosis/ferroptosis regulated cell death pathway in the AD brain.
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