Abstract
Amyloid beta (Aβ) 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 Aβ. It was found that intracellular Aβ 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.
Highlights
Introduction A hallmark ofAlzheimer’s disease (AD) is the accumulation of amyloid beta (Aβ) in extracellular plaques in the brains of patients
In order to identify the molecular mechanism(s) by which intracellular Aβ is toxic to neurons, we carried out Official journal of the Cell Death Differentiation Association
We report here that intracellular accumulation of Aβ causes nerve cell death via oxytosis/ ferroptosis
Summary
Alzheimer’s disease (AD) is the accumulation of amyloid beta (Aβ) in extracellular plaques in the brains of patients. Intraneuronal accumulation of Aβ has been detected in nerve cell lines and transgenic mouse models of AD (reviewed in[2,3,4,5,6]). This accumulation of Aβ can take place in a variety of subcellular compartments, including endosomes, multivesicular bodies, lysosomes, mitochondria, endoplasmic reticulum, Golgi apparatus, and cytosol[3,4]. Toxic effects on specific physiological processes have been reported, such as synaptic disruption, inhibition of the ubiquitin-proteasome system, mitochondrial dysfunction, and activation of pro-inflammatory responses[6,7,8], the exact molecular mechanism underlying the intraneuronal Aβ toxicity remains unclear
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