CDGSH Iron Sulfur Domain 1 Relieves Neuronal Ferroptosis via Activating AMPK Pathway in Alzheimer's Disease

CDGSH iron sulfur domain 1 (CISD1) plays important roles in regulating cellular iron and reactive oxygen species (ROS) homeostasis. This study aimed to investigate the effect of CISD1 on neuronal ferroptosis in Alzheimer's disease (AD) cellular models, and the implication of AMPK pathway during this process. CISD1 expression in brain tissues from AD patients and controls was obtained from AlzData public database. HT22 and SH-SY5Y cells were challenged with amyloid-beta (Aβ) to construct AD cellular models. CISD1 or negative-control (NC) overexpression plasmids were transfected into AD cellular models; afterwards, Compound C (an AMPK activator) was added. CISD1 expressions in entorhinal cortex, hippocampus, temporal cortex, and frontal cortex tissues were decreased in AD patients versus controls via AlzData public database analysis. CISD1 expression was also downregulated in AD cellular models versus control cells. Interestingly, cell viability and SLC7A11 and GPX4 expressions were lower, but ROS and Fe²⁺ levels were higher in AD cellular models versus control cells, indicating an enhanced neuronal ferroptosis in AD. Subsequently, CISD1 overexpression plasmids raised cell viability and SLC7A11 and GPX4 expressions, while decreased ROS and Fe²⁺ levels compared with NC overexpression plasmids in AD cellular models. CISD1 overexpression plasmids also facilitated the phosphorylation of AMPK to activate this pathway compared to NC overexpression plasmids. Moreover, the addition of Compound C not only promoted the neuronal ferroptosis, but also attenuated the effect of CISD1 overexpression plasmids on regulating neuronal ferroptosis compared with the absence of Compound C in AD cellular models. Collectively, CISD1 represses neuronal ferroptosis by activating the AMPK pathway in AD cellular models, shedding a light on its potential engagement in the AD pathogenesis.