Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

Afridi, Ruqayya; Kim, Jong‐Heon; Rahman, Habibur; Suk, Kyoungho

doi:10.3389/fncel.2020.00020

Cited by 69 publications

(57 citation statements)

References 180 publications

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“…The mitochondrial perturbations observed in activated microglia can propagate signals to other cell types, including astrocytes and neurons, further exaggerating the disease outcome (Joshi et al, 2019 ). Increased glycolysis and upregulated expression of glucose transporters as well as glycolytic enzymes in activated microglia are a well-established phenomenon (Afridi et al, 2020 ). Increased microglial glycolysis is often coupled with the increased secretion of proinflammatory cytokines, exacerbating neurotoxicity, and escalating ongoing neurodegeneration.…”

Section: Microglial Phenotypes Associated With Aging and Neurodegenermentioning

confidence: 99%

Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration

Lee

Suk

2020

Front. Cell. Neurosci.

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Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review article, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.

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Section: Microglial Phenotypes Associated With Aging and Neurodegenermentioning

confidence: 99%

Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration

Lee

Suk

2020

Front. Cell. Neurosci.

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“…Nevertheless, there was an increased population of other cell types, especially in the 400 mg/kg RV group, a possibility that these were small size neurons and glial cells. Neurons of the hipoocampus may not proliferate, but astrocytes and microglia are known to increase during insults (Afridi et al, 2020). Thus, this population of cells may have been more of astrocytes and/or microglia.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Hippocampal Histomorphology Following R. vomitoria Root Extract Treatment

Ekong

Ekpene

Nwakanma

et al. 2020

IJMSS

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Rauwolfia vomitoria Afzel. is an antipsychotic plant used by several African communities in the management of psychiatric conditions with good outcomes. Concerns about its dosages on brain activity lead to this investigation of its action on the hippocampal microstructure. Twenty-four adult male Wistar rats of average weight 200 g, were assigned into four groups (n = 6): control; 200, 300 and 400 mg/kg body weight of RV root bark extract, respectively. The administration was once daily, and orally for seven days. Daily observation of the animals was done till on day eight when they were sacrificed after deep anaesthesia. Each brain was processed for histology and immunohistochemical studies. Animals in the 200, 300 and 400 mg/kg RV groups appeared generally dull and drowsy, and barely fed. Their hippocampal histology showed neuronal atrophy and karyorrhexis, with no difference in cell count, although the pyramidal cell numbers decreased in the 300 and 400 mg/kg RV groups. Neuron-specific enolase decreased in the 400 mg/kg RV group, while neurofilament decreased in all test groups. Glial fibrillary acidic protein expression and density increased in the 200 and 300 mg/kg RV groups, but not the 400 mg/kg RV group, all compared with the control group. The given doses of RV root bark extract in adult Wistar rats showed sedative activities with hippocampal histopathological changes, which may not be reversible, thereby leading to the hippocampal functional deficit.

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“…Of these proteins, 32 were shared between SCZ and BIP, and most of them related to mitochondrial electron transport, response to reactive oxygen species and glycolysis [72]. Interestingly, immunological status, energy metabolism, and neurotransmission exert strong influence on each other and are highly dependent on neuron-glia interactions [73].…”

Section: Genetics Of Schizophrenia and Bipolar Disordermentioning

confidence: 99%

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

Assis

Szabó

Osete

et al. 2021

Cells

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Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.

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Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

Cited by 69 publications

References 180 publications

Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration

Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration

Characterization of Hippocampal Histomorphology Following R. vomitoria Root Extract Treatment

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

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