This is a new review from Florey Institute about ferroptosis in AD giving new possibilities in AD treatments. I could read only the abstract but it looks like iron chelation would be included in the paper. Prof. Masters with his new PBT2 license is not among the authors but he has, for sure, all this knowledge when he is planning his new studies with PBT2 and Acyl Hydrazone.

Antioxid Redox Signal

. 2023 May 22.

doi: 10.1089/ars.2023.0318. Online ahead of print.

Striking a NRF2: The rusty and rancid vulnerabilities toward ferroptosis in Alzheimer's disease

Darius J R Lane ^{1 2}, Francesca Alves ^{1 3}, Scott Ayton ^{1 4}, Ashley I Bush ^{1 5}

Affiliations expand

• PMID: 37212212

DOI: 10.1089/ars.2023.0318

Abstract

The lack of disease-modifying treatments for Alzheimer's disease (AD) that substantially alter the disease course 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-dysregulating and redox dysregulation in AD could lead to new therapeutic targets with disease-modifying potential. Ferroptosis, which was named in 2012, is a necrotic form of regulated cell death (RCD) that depends on both iron and lipid peroxidation. While it is distinct from other types of RCD, 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 seleno-enzyme, glutathione peroxidase 4. An expanding network of protective proteins and pathways have also being identified complement GPX4 in the protection of cells against ferroptosis, with a central role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). 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. Finally, we discuss how the ferroptosis paradigm in AD is providing a new spectrum of therapeutic targets.