The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer's disease (AD) pathogenesis remains unclear, despite its high incidence.
• Ferroptosis, a form of regulated cell death, is implicated in AD, with ORMDL3 identified as a potential contributor.
• The precise mechanisms by which ORMDL3 influences ferroptosis in AD are not fully understood.

Purpose of the Study:

• To investigate the role of ORMDL3 in ferroptosis within Alzheimer's disease models.
• To elucidate the potential molecular mechanisms underlying ORMDL3-mediated ferroptosis in AD.
• To explore ORMDL3 as a potential therapeutic target for AD.

Main Methods:

• Utilized APPswe/PS1dE9 transgenic mice and C57BL/6 mice as AD models.
• Employed murine microglial BV-2 cells for in vitro studies.
• Measured ORMDL3 mRNA and protein expression in patient serum and mouse brain tissue.
• Analyzed the involvement of the PERK/ATF4/HSPA5 signaling pathway.

Main Results:

• ORMDL3 mRNA expression was upregulated in serum from AD patients and hippocampal tissue from AD mouse models.
• Serum ORMDL3 levels correlated positively with cognitive impairment scores (ADL, MoCA, MMSE) and homocysteine levels in AD patients.
• ORMDL3 overexpression promoted oxidative stress and ferroptosis in AD models, mediated by the PERK/ATF4/HSPA5 pathway.

Conclusions:

• ORMDL3 plays a significant role in promoting oxidative stress and ferroptosis in Alzheimer's disease.
• The PERK/ATF4/HSPA5 pathway is a key mechanism through which ORMDL3 exerts its effects in AD.
• ORMDL3 represents a novel potential therapeutic target for managing ferroptosis in Alzheimer's disease.