Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia

Wijtenburg, S. Andrea; Kapogiannis, Dimitrios; Korenic, Stephanie A.; Mullins, Roger J.; Tran, Joyce; Gaston, Frank; Chen, Shuo; Mustapić, Maja; Hong, L. Elliot; Rowland, Laura M.

doi:10.1016/j.schres.2019.01.031

Cited by 48 publications

(41 citation statements)

References 74 publications

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“…Interestingly, modifications in the concentration of markers of insulin resistance were also found in EVs derived from the plasma of patients suffering schizophrenia. By magnetic resonance spectroscopy an increase of glucose concentration in the brain of these individuals was noticed [272]. Moreover, it was shown that the increase of insulin resistance and of glucose concentration are related to memory deficit [272].…”

Section: Evs In Neuropathologymentioning

confidence: 98%

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

Schiera

Liegro

2019

IJMS

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Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

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Section: Evs In Neuropathologymentioning

confidence: 98%

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

Schiera

Liegro

2019

IJMS

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“…Extracellular vesicles contain cargo that reflects the content of the vesicle's cellular origin, providing a novel avenue for probing intracellular signaling processes including neuroinflammatory pathways that are putatively implicated in neuropsychiatric disorders. This methodology has been used to directly assess neuronal inflammatory biomarkers in mild traumatic brain injury [25,26], as well as biomarkers from other pathways in disparate conditions, such as Alzheimer's disease (AD) and schizophrenia [27,28]. In addition, NEVs have been used as a source of biomarkers that predict neuronal-specific molecular target engagement and response to experimental treatments in clinical trials (e.g., in Parkinson's disease [21], AD [29], and cancer [30]), revealing concerted engagement of entire signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

Mansur

Delgado-Peraza

Subramaniapillai

et al. 2020

Cells

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Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab’s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab’s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα)α (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = −0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

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“…Insulin resistance is associated with the inability of target tissues to increase glucose uptake in response to insulin [52]. Insulin resistance of brain tissues can reduce glucose levels in the brain by glucose-transporter-dependent pathways (among others, GLUT4), which together cause disturbed neurotransmission and disease progression [53]. Obese patients treated with atypical neuroleptics, in addition to insulin resistance, develop an additional phenomenon of lipotoxicity, leading to an increase in the level of free fatty acids (FFA) in the plasma, which is explained by their competition with glucose as oxidative substrates [54].…”

mentioning

confidence: 99%

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

et al. 2020

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Schizophrenia is a neurodevelopmental disorder featuring chronic, complex neuropsychiatric features. The etiology and pathogenesis of schizophrenia are not fully understood. Oxidative-antioxidant imbalance is a potential determinant of schizophrenia. Oxidative, nitrosative, or sulfuric damage to enzymes of glycolysis and tricarboxylic acid cycle, as well as calcium transport and ATP biosynthesis might cause impaired bioenergetics function in the brain. This could explain the initial symptoms, such as the first psychotic episode and mild cognitive impairment. Another concept of the etiopathogenesis of schizophrenia is associated with impaired glucose metabolism and insulin resistance with the activation of the mTOR mitochondrial pathway, which may contribute to impaired neuronal development. Consequently, cognitive processes requiring ATP are compromised and dysfunctions in synaptic transmission lead to neuronal death, preceding changes in key brain areas. This review summarizes the role and mutual interactions of oxidative damage and impaired glucose metabolism as key factors affecting metabolic complications in schizophrenia. These observations may be a premise for novel potential therapeutic targets that will delay not only the onset of first symptoms but also the progression of schizophrenia and its complications.

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Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia

Cited by 48 publications

References 74 publications

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

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