Perturbed iron biology in the prefrontal cortex of people with schizophrenia

Abstract

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Brain Iron Homeostasis and Mental Disorders

“…Magnetic resonance brain neuroimaging research in schizophrenia patients has shown elevated brain iron levels in different brain regions, including the putamen and thalamus [118,119]. In addition, increased iron levels were also found in the prefrontal cortex of people with schizophrenia, as measured by inductively coupled plasma-mass spectrometry (ICP-MS) and Western Blots [60]. This emerging evidence suggests a potential association between iron overload and schizophrenia in individuals or in post-mortem human brain samples.…”

“…In the context of mental health, IRP2, particularly through its regulation of ferritin expression, has been significantly associated with schizophrenia. It has been observed that IRP2 is marginally overexpressed in the prefrontal cortex of individuals with schizophrenia, leading to lower levels of ferritin expression among patients with this condition [60]. Furthermore, mutations in other genes involved in controlling brain iron homeostasis, such as ferritin and CP, can also contribute to disorders of brain iron metabolism and impact myelin synthesis [61,62].…”

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…It is also a cofactor for the biosynthesis of tyrosine hydroxylase and tryptophan hydroxylase, enzymes involved in the synthesis of DA and serotonin (5-HT) respectively. In the gut, DA acts as a microbial siderophore which clears Fe 2+ from the microenvironment, lowering the risk of ferroptosis [38,39].…”

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…It is also a cofactor in the biosynthesis of tyrosine hydroxylase and tryptophan hydroxylase, enzymes involved in the synthesis of DA and serotonin (5-HT), respectively. In the gut, DA acts as a microbial siderophore, which clears Fe 2+ from the microenvironment, lowering the risk of ferroptosis [ 38 , 39 ].…”