686. SCHIZOPHRENIA-LIKE ENDOPHENOTYPES IN AMYLOID PRECURSOR PROTEIN KNOCK OUT MICE

Abstract Background Schizophrenia is a complex mental health condition that impacts an estimated 1% of the global population. The exact causes remain largely unclear. Recent findings from our research group have found evidence for the presence of iron dyshomeostasis and ubiquitin protein stress in the prefrontal cortex (PFC) of a group of individuals with schizophrenia. These iron-perturbations were characterised by excess iron, elevated levels of ubiquitinated proteins and downregulation of Amyloid Precursor Protein (APP). Remarkably, APP knock out mice accumulate iron in the brain and display schizophrenia-like endophenotypes. Aims & Objectives This study aims to evaluate behavioral, brain structural and protein changes in the APP knock out (APP-KO) mice. Method We analyzed the iron levels in brain samples from age-matched control and APP-KO mice by ICP-MS. Protein levels were assessed by Western blot. The behavior of these animals was monitored by prepulse inhibition assessment (a schizophrenia phenotype) and clasping scores. Brain structural changes were monitored by magnetic resonance imaging. Results We found that the frontal cortex of these animals are characterized by elevated iron in the soluble fraction and accumulation of ubiquitinated proteins in the insoluble fraction. In addition, we detected altered levels of proteins involved in iron homeostasis. Surprisingly, we observed that male APP-KO mice displayed increased startle response and high clasping scores. Importantly, these animals expressed a specific and significant decrease in the volume of thalamus. Discussion & Conclusions Iron dyshomeostasis can disrupt neurodevelopment, leading to oxidative and protein stress, which in turn may lead to neuronal dysfunction, culminating in ferroptosis and neurodegeneration. Here we identify novel schizophrenia-like endophenotypes in an animal model exhibiting brain iron accumulation driven by the absence of APP. These results suggest that stressors in ubiquitin signalling, iron metabolism and APP homeostasis are candidate factors that could impact the neurobiology of schizophrenia.