PMID- 37212212
OWN - NLM
STAT- MEDLINE
DCOM- 20230719
LR  - 20230719
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Linking)
VI  - 39
IP  - 1-3
DP  - 2023 Jul
TI  - Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in 
      Alzheimer's Disease.
PG  - 141-161
LID - 10.1089/ars.2023.0318 [doi]
AB  - Significance: The lack of disease-modifying treatments for Alzheimer's disease 
      (AD) that substantially alter the course of the disease highlights the need for 
      new biological models of disease progression and neurodegeneration. Oxidation of 
      macromolecules within the brain, including lipids, proteins, and DNA, is believed 
      to contribute to AD pathophysiology, concomitant with dysregulation of 
      redox-active metals, such as iron. Creating a unified model of pathogenesis and 
      progression underpinned by iron dysregulation and redox dysregulation in AD could 
      lead to new therapeutic targets with disease-modifying potential. Recent 
      Advances: Ferroptosis, which was named in 2012, is a necrotic form of regulated 
      cell death that depends on both iron and lipid peroxidation. While it is distinct 
      from other types of regulated cell death, ferroptosis is regarded as being 
      mechanistically synonymous with oxytosis. The ferroptosis paradigm has great 
      explanatory potential in describing how neurons degenerate and die in AD. At the 
      molecular level, ferroptosis is executed by the lethal accumulation of 
      phospholipid hydroperoxides generated by the iron-dependent peroxidation of 
      polyunsaturated fatty acids, while the major defensive protein against 
      ferroptosis is the selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding 
      network of protective proteins and pathways have also been identified to 
      complement GPX4 in the protection of cells against ferroptosis, with a central 
      role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). Critical 
      Issues: In this review, we provide a critical overview of the utility of 
      ferroptosis and NRF2 dysfunction in understanding the iron- and lipid 
      peroxide-associated neurodegeneration of AD. Future Directions: Finally, we 
      discuss how the ferroptosis paradigm in AD is providing a new spectrum of 
      therapeutic targets. Antioxid. Redox Signal. 39, 141-161.
FAU - Lane, Darius J R
AU  - Lane DJR
AUID- ORCID: 0000-0001-8725-6903
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental 
      Health, The University of Melbourne, Parkville, Victoria, Australia.
FAU - Alves, Francesca
AU  - Alves F
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental 
      Health, The University of Melbourne, Parkville, Victoria, Australia.
FAU - Ayton, Scott J
AU  - Ayton SJ
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental 
      Health, The University of Melbourne, Parkville, Victoria, Australia.
FAU - Bush, Ashley I
AU  - Bush AI
AD  - Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental 
      Health, The University of Melbourne, Parkville, Victoria, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
RN  - 0 (NF-E2-Related Factor 2)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Humans
MH  - *Ferroptosis
MH  - Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism
MH  - *Alzheimer Disease
MH  - NF-E2-Related Factor 2/metabolism
MH  - Cell Death/genetics
MH  - Lipid Peroxidation/genetics
MH  - Iron/metabolism
OTO - NOTNLM
OT  - NRF2
OT  - astrocyte
OT  - cell death
OT  - ferroptosis
OT  - iron
OT  - lipid peroxidation
OT  - neurodegeneration
OT  - neuroinflammation
OT  - neuron
EDAT- 2023/05/22 06:42
MHDA- 2023/07/19 06:42
CRDT- 2023/05/22 05:53
PHST- 2023/07/19 06:42 [medline]
PHST- 2023/05/22 06:42 [pubmed]
PHST- 2023/05/22 05:53 [entrez]
AID - 10.1089/ars.2023.0318 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2023 Jul;39(1-3):141-161. doi: 10.1089/ars.2023.0318.