For the past decade, several lines of evidence have shown a direct role for oxidative stress in the pathology of schizophrenia (SZ). Although peripheral changes associated with oxidative stress may be useful to establish biomarkers for the disease, connecting such peripheral changes to brain dysfunction has not yet been fully established. Furthermore, there is a need to develop high throughput assays for measuring such peripheral changes. We recently found that oxidative stress-associated endogenous autofluorescence (AF) is aberrantly augmented in SZ cells. AF is regulated by the GAPDH stress cascade, and the extent of AF is negatively correlated with cognitive flexibility evaluated by the Wisconsin Card Sorting Test. Meanwhile, we have recently found that the selectively activated GAPDH stress cascade in microglia in the prefrontal cortex is likely to mediate cognitive inflexibility in an oxidative stress-associated mouse model. We have observed that expression of Cd11b (a key factor for microglia to target to synapse) is regulated by the GAPDH stress cascade in this mouse model. Based on these promising preliminary data, we hypothesize that activation of the GAPDH stress cascade and associated altered AF triggers pathological changes in microglia, which in turn affects synaptic connectivity in the prefrontal cortex that underlies cognitive flexibility. To address this hypothesis, we propose the following three aims: 1) to establish a high throughput assay that measures cellular AF from human blood samples; 2) to identify specific cognitive domain(s) that is correlated with and predicted by augmented AF in blood cells; and 3) to identify a molecular mechanism by which the GAPDH stress cascade mediates cognitive inflexibility in an oxidative stress-associated animal model. Through these three Aims, we seek the translational potential of intervening in the GAPDH stress cascade to ameliorate cognitive deficits by using AF in blood cells as an objective high throughput marker.
Based on promising preliminary data, we study cellular autofluorescence detected by high throughput screening in blood cells as a possible predictor for cognitive flexibility in schizophrenia and related disorders. We also address its molecular mechanisms underlying the cellular autofluorescence-associated cognitive flexibility in an animal model.
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