¹The Florey Institute of Neuroscience and Mental Health, Mental Health Mission, Melbourne, Australia, ²The University of Melbourne & Melbourne Health, Department of Psychiatry, Melbourne, Australia, ³Hadassah-Hebrew University Medical Center, Department of Adult Psychiatry and the Biological Psychiatry Laboratory, Jerusalem, Israel, ⁴Monash University, Psychiatry Monash Health, Melbourne, Australia, ⁵State University of New York (SUNY) Upstate Medical University, Department of Neuroscience and Physiology, New York, United States, ⁶Neuroscience Research Australia, Schizophrenia Research Laboratory, Sydney, Australia, ⁷University of Calgary, Departments of Medical Genetics, Psychiatry, Physiology & Pharmacology, Calgary, Canada, ⁸University of Calgary, Hotchkiss Brain Institute, Calgary, Canada, ⁹King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom, ¹⁰Monash University, Monash Institute of Pharmaceutical Sciences (MIPS), Melbourne, Australia

Background: Schizophrenia is a major neuropsychiatric disorder that is often disabling and associated with progressive brain changes, which have been linked to oxidative stress. Iron, the most abundant transition metal in the brain, is critical for key neurobehavioral pathways. However, labile iron is redox-sensitive, and its excess can provoke neuroinflammation and neurodegeneration. We have previously reported that iron is increased and iron related proteins are perturbed in schizophrenia prefrontal tissue postmortem.

Aims & Objectives: This study sought to evaluate whether the Amyloid Precursor Protein (APP), a protein that faciliates export of intracellular iron, is altered in prefrontal cortex (PFC) of individuals with schizophrenia.

Method: Specimens from the PFC of individuals with schizophrenia (n=86) and matched controls (n=85) were obtained from three independent brain tissue resources. The main biological metals (iron, copper, zinc) and relevant proteins (ferritin, amyloid precursor protein [APP] and glutathione peroxidase 4 [GPX4]) were quantified in brain supernatant fractions by ICP-MS and infrared Western blots, respectively.

Results: Protein levels of ferritin, which stores iron in a redox-inactive form, and of APP were decreased in schizophrenia patients (-0.63 SDs, p<0.0001, and -0.49 SDs, p=0.001, respectively), and the iron-APP relationship was grossly distorted in the patient group (t₁₆₀=-3.44, p=0.0008). Copper levels were not affected by disease status and zinc was marginally higher among patients (0.28 [95%CI 0.03 to 0.54]. As a predictive tool, a labile iron index based on the interaction between tissue iron, ferritin and APP could discriminate between patients and controls (AUCROC=0.733, p<0.0001). Finally, protein levels of GPX4, which serves as the checkpoint for ferroptosis, were lower in patients (-0.326 SDs, p=0.031).

Discussion & Conclusions: We previously reported a conspicuous elevation of labile iron in PFC tissue of schizophrenia patients, which is most prominent in young-adulthood and coincides with the most prominent progressive brain changes reported in the disorder. Coupled with an apparent deficit in mitigating iron-dependent accumulation of toxic lipid peroxides, our findings are consistent with a mechanistic link between iron dyshomeostasis and neuroprogressive changes and introduce the therapeutic potential of targeting ferroptosis susceptibility during the early phases of schizophrenia.