Now that we have positive ATH201 results in MSA with almost physiological iron chelator ATH434 blocking ferroptosis and with that slowing down brain atrophy, I will return with this paper below ATH434 possibilities in AD.

This paper is from the Florey Institute by prof Bush and Dr. Ayton et al. It was already e-published in 2022 but in print only 1 year ago. I already posted it over 2y ago but only now with 201 results, it becomes much more important.

The biggest risk of getting AD is to have the ApoE4 gene. The paper found that apolipoproteins are iron chelators but ApoE4 is the worst of these 4 types and it looks like it could be the reason why humans with this gene are prone to get AD.

To me, it looks like the ApoE4 people need stronger but almost physiological iron chelator ATH434. Old iron chelators destroy mitochondria ( Bush et al 2024) .

This is a free paper. The Florey people know the 201 results. Bush is an owner of ATH stocks. It would be great if Stamler would have animal experiment results about ATH434 in AD.

Mol Psychiatry

. 2024 Feb;29(2):211-220.

doi: 10.1038/s41380-022-01568-w. Epub 2022 Apr 28.

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy

Abdel Ali Belaidi ¹, Shashank Masaldan ¹, Adam Southon ¹, Pawel Kalinowski ¹, Karla Acevedo ¹, Ambili T Appukuttan ¹, Stuart Portbury ¹, Peng Lei ², Puja Agarwal ³, Sue E Leurgans ³, Julie Schneider ³, Marcus Conrad ^{4 5}, Ashley I Bush ^{# 6}, Scott Ayton ^{# 7}

Affiliations Expand

• PMID: 35484240

PMCID: PMC9757994 DOI: 10.1038/s41380-022-01568-w

Abstract

Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC₅₀ ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.