Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer’s Disease: Current Evidence and Future Avenues

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, and autophagy plays important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD, and discussed the interplays existing between energy crisis, autophagy and ferroptosis. In addition, we highlighted the potential network that autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new strategies for treating AD, meanwhile, the energy crisis in the progression of AD should gain more attention.

Bibliometric analysis of research on Alzheimer’s disease and non-coding RNAs: Opportunities and challenges

“…It has been found that down-regulation of miR-22 can significantly alleviate the apoptosis of PC-12 cells induced by LPS and achieve the purpose of treating diseases ( Wang Y. et al, 2022 ). Of course, there are many types of nerve cell death, including apoptosis, pyroptosis, necrosis, and ferroptosis ( He et al, 2022 ; Jin et al, 2022 ; Mangalmurti and Lukens, 2022 ). Whether ncRNAs can achieve the purpose of treating diseases by regulating different types of death is also worthy of further study in the future ( Li W. et al, 2022 ; Wang J. et al, 2022 ).…”