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

• DOI: 10.1038/s41418-022-01003-1
• Publication Date: 2022-04-21T15:07:54Z
• Authors: Mark A. Greenough; Darius J. R. Lane; Rachelle Balez; Helena Targa Dias...; Zhiwen Zeng; Katherine Ganio; Christopher A. Mc...; Karla Acevedo; Abdel Ali Belaidi; Jari Koistinaho; Lezanne Ooi; Scott Ayton; Ashley I. Bush
• Keywords: Selenoprotein; GPX4

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