This paper by prof. AI Bush et al "demonstrated that genetic or pharmacological disruption of PS (presenilin) function sensitized cells to ferroptosis, but not apoptosis, which invites renewed interpretations for the role of PS in AD".

And further: "our studies demonstrate the potential for presenilin mutations to promote neurodegeneration irrespective of Aβ, which may or may not be an additional toxic lesion. Agents that rescue ferroptosis such as iron chelators, brain-accessible selenium treatments (not dependent on SELENOP), glutathione precursors and radical trapping agents may therefore have therapeutic potential for AD."


This is a free paper: Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations | Cell Death & Differentiation (nature.com)

Here is the abstract:

Cell Death Differ

. 2022 Nov;29(11):2123-2136.

doi: 10.1038/s41418-022-01003-1. Epub 2022 Apr 21.

Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations

Mark A Greenough ^{# 1}, Darius J R Lane ^{# 1}, Rachelle Balez ^{2 3}, Helena Targa Dias Anastacio ^{2 3}, Zhiwen Zeng ⁴, Katherine Ganio ⁵, Christopher A McDevitt ⁵, Karla Acevedo ¹, Abdel Ali Belaidi ¹, Jari Koistinaho ^{6 7}, Lezanne Ooi ^{2 3}, Scott Ayton ⁸, Ashley I Bush ⁹

Affiliations expand

• PMID: 35449212

PMCID: PMC9613996 DOI: 10.1038/s41418-022-01003-1Free PMC article

Abstract

Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer's disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.

© 2022. The Author(s).