Fig. 5: A hypothesis of how loss of γ-secretase function causes ferroptotic stress.

a (1) Presenilins combine with other proteins of the γ-secretase complex to (2) cleave Notch-1, releasing the intracellular domain of Notch-1 (NICD). (3) NICD translocates to the nucleus and binds the co-activator, RBPJκ, to transcribe LRP8. (4) LRP8 is the neuronal receptor for the selenium transport protein, SELENOP. (5) Following internalization, SELENOP is degraded in the lysosome, releasing selenocysteine (Sec). Sec is decomposed to selenide by Sec lyase (SCLY), which is used to synthesize Sec-tRNA^[Ser]Sec in a pathway involving selenophosphate synthetase 2 (SEPHS2), ultimately incorporating Sec into de novo translated Glutathione Peroxidase 4 (GPX4). (6) GPX4, which detoxifies lethal iron-catalyzed lipid hydroperoxides (LOOH), is a critical checkpoint in the ferroptosis pathway. Diminished GPX4 activity causes ferroptosis. Created with BioRender.com. b Model for ferroptosis causing AD. Brain iron levels rise needlessly but universally with aging. The burden of brain iron increases the chance of ferroptosis occurring, held in better check by wild type PS than mutant PS. As a result, neuroferroptosis commences at an earlier age in people expressing mutant PS (familial AD) than the typical age of onset of non-familial AD in people expressing wild type PS. The insert shows the canonical ferroptosis events: cytoplasmic Fe²⁺ reacts with polyunsaturated fatty acids (PUFAs) to generate lipid peroxides, which, beyond a certain threshold, can disrupt the cell membrane. PS mutations suppress the expression of GPX4, which is a major checkpoint enzyme that prevent lipid peroxide accumulation from reaching lethal levels.