This is a collaboration paper by many centers, and it looks like the Florey Institute has been doing the main part of it: AI Bush and S Ayton. These two scientists were also the main authors of the paper demonstrating that Deferiprone does not work in AD (January 2025).

Their conclusion is: "This study reveals a new mechanistic link between two well-established pathophysiological changes in AD, energy insufficiency and oxidative stress, and exposes a druggable pathway to slow neurodegeneration".

I cannot avoid thinking (after the abstracts and papers by Prof Kosman on ATH434) that "the druggable pathway" to improve the lack of energy and control of oxidative stress could be to use ATH434.

Adv Sci (Weinh)

. 2025 Jul 8:e04175.

doi: 10.1002/advs.202504175. Online ahead of print.

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis

Francesca Alves ^{1 2}, Darius Lane ¹, Adam Wahida ³, Md Jakaria ¹, Pawel Kalinowski ¹, Adam Southon ¹, Abdel Ali Belaidi ¹, Teresa Samperi-Esteve ⁴, Triet Phu Minh Nguyen ¹, Peng Lei ⁵, Marcus Krueger ^{6 7}, Stefan Mueller ⁸, Marcus Conrad ^{3 9}, Puja Agarwal ¹⁰, Sue E Leurgans ¹⁰, Julie Schneider ¹⁰, Ashley I Bush ^{1 2}, Scott Ayton ^{1 2}

Affiliations Expand

• PMID: 40625200

DOI: 10.1002/advs.202504175

Abstract

Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202504175