Pentosidine modification of neuronal proteins induces dendritic spine enlargement in vitro.

Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive dysfunction. Recent clinical studies have identified elevated blood levels of pentosidine (PEN), an advanced glycation end product (AGE), in 40 % of patients with schizophrenia, a subgroup associated with severe cognitive dysfunction and resistance to antipsychotic treatment. However, the biological effects of PEN and its contribution to pathophysiology of schizophrenia remain poorly understood. In this study, we established a novel cellular model that recapitulates intracellular PEN accumulation in mouse primary neurons following treatment with glucuronic acid, a precursor of PEN, identified in patients with schizophrenia. Using this model, we performed comprehensive analyses, including liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics, transcriptomics, and morphological assessments. Our findings revealed that PEN modified intracellular neuronal proteins, including histones and synaptic scaffold proteins such as the synaptic Ras GTPase activating protein 1 (SynGAP). These PEN modifications lead to epigenetic dysregulation and Ras-related activation of the C3 botulinum toxin substrate 1 (Rac1), resulting in enlargement of dendritic spines without changes in spine density. This phenotype is similar to that observed in genetic models of schizophrenia, which are associated with cognitive deficits and synaptic dysfunction. These results identify dendritic spine enlargement as a novel pathophysiological feature associated with PEN accumulation and provide mechanistic insights into treatment-resistant cognitive impairment in this schizophrenia. This cellular model offers a promising platform for the development of targeted therapeutics aimed at PEN-associated synaptic dysfunction.