This is a paper from Holland with also authors from the Florey Institute.

"In this study, we demonstrated that AD-related Aβ pathology is associated with changes in protein expression of ferroptosis-related proteins in the human brain. In addition, revealing that ferrostatin-1 treatment can mitigate Aβ-related effects on lipid peroxidation, and iron homoeostasis in AD iPSCs-derived brain organoids further supports the hypothesis that in AD, ferroptosis is linked with Aβ pathology".

In their abstract, they say: " Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions".

IMO, there has been a clear causal relationship between iron and Parkinson's disease but in AD this has not been so clear although the AD brain has iron overload, and we can see a problem in energy metabolism most likely related also to iron overload.


Alterity has ATH434, almost a physiological iron chelator and most likely Alterity has tested it in AD animal models as they tell in their Annaular report. 434 needs to be safe and safer than other iron chelators on the mitochondrial level as it looks in the abstracts by Kosman et al. IMO ATH434 is soon ready for an AD clinical study.

Cell Death Dis

. 2024 Oct 28;15(10):782.

doi: 10.1038/s41419-024-07152-0.

The link between amyloid β and ferroptosis pathway in Alzheimer's disease progression

Naďa Majerníková ^{1 2}, Alejandro Marmolejo-Garza ^{1 3}, Casandra Salinas Salinas ¹, Minh D A Luu ¹, Yuequ Zhang ¹, Marina Trombetta-Lima ^{1 4}, Tamara Tomin ⁵, Ruth Birner-Gruenberger ⁵, Šárka Lehtonen ^{6 7}, Jari Koistinaho ⁷, Justina C Wolters ⁸, Scott Ayton ⁹, Wilfred F A den Dunnen ¹⁰, Amalia M Dolga ^{11 12}

Affiliations Expand

• PMID: 39468028

PMCID: PMC11519607 DOI: 10.1038/s41419-024-07152-0

Abstract

Alzheimer's disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease's impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.