Glial-neuron crosstalk in health and disease: A focus on metabolism, obesity, and cognitive impairment

Henn, Rosemary E.; Noureldein, Mohamed; Elzinga, Sarah; Kim, Bhumsoo; Savelieff, Masha G.; Feldman, Eva L.

doi:10.1016/j.nbd.2022.105766

Cited by 38 publications

(34 citation statements)

References 133 publications

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“…Chronic inflammation and immune system dysregulation are common in individuals with obesity and in individuals who fall along the continuum of metabolic dysfunction from prediabetes to frank type 2 diabetes ( 7 ). Previous studies investigating the effects of metabolic dysfunction on the CNS report dysregulation of immune and inflammatory mechanisms, typically increased glial activation and elevated production of CNS pro-inflammatory proteins and mediators ( 8 – 10 ). Specifically, a high-fat diet (HFD) in mice induces an inflammatory phenotype in microglia, the resident immune cells of the CNS ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

cGAS/STING and innate brain inflammation following acute high-fat feeding

et al. 2022

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Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.

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Section: Introductionmentioning

confidence: 99%

cGAS/STING and innate brain inflammation following acute high-fat feeding

et al. 2022

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“…Axons are insulated from extracellular fluid by several layers of myelin sheets formed by oligodendroglia that limit their access to extracellular glucose and lactate. Therefore, lactate is supplied by surrounding oligodendroglial processes through their MCT1 to peri-axonal space, from where it is taken up by axonal MCT2 and used for acetyl-CoA and ATP synthesis in axonal mitochondria [ 69 , 70 ]. Fractions of lactate and glucose are also provided by astrocytes that contact axons at nodes of Ranvier’s.…”

Section: Origin and Metabolic Role Of Axonal Acetyl-coamentioning

confidence: 99%

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

Jankowska-Kulawy

Klimaszewska-Łata

Gul-Hinc

et al. 2022

IJMS

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The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.

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“…An increasing number of studies indicate that patients with type 2 DM are also between 1.5 and 3 times more likely to develop AD or vascular dementia [ 131 ]. Although the pathophysiological mechanisms of the increased risk of dementia due to the presence of DM are diverse and controversial, central insulin resistance, inflammation, and oxidative stress have mainly been proposed as etiologic mechanisms [ 132 ]. Insulin receptors, insulin-like growth factor (IGF)-1 receptors, and their post-receptor signaling partners are distributed throughout the brain [ 133 ].…”

Section: The Relationship Between Metabolic Dysfunction and Dementiamentioning

confidence: 99%

“…DM adversely affects oligodendrocytes, astrocytes, and microglia in the brain [ 132 ]. Conditions of diet-induced obesity or dysregulated metabolism lead to multiple pathologic changes in glia, including oligodendrocyte loss and impaired myelination [ 145 ], alterations in astrocyte autophagy [ 146 ], release of neurotransmitters [ 147 ], and activation of microglia [ 148 ].…”

Section: The Relationship Between Metabolic Dysfunction and Dementiamentioning

confidence: 99%

“…Conditions of diet-induced obesity or dysregulated metabolism lead to multiple pathologic changes in glia, including oligodendrocyte loss and impaired myelination [ 145 ], alterations in astrocyte autophagy [ 146 ], release of neurotransmitters [ 147 ], and activation of microglia [ 148 ]. These pathological changes may impair glia–neuron metabolic interactions and disrupt the energy supply chain to neurons, resulting in neuronal damage that may lead to cognitive impairment [ 132 ].…”

Section: The Relationship Between Metabolic Dysfunction and Dementiamentioning

confidence: 99%

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The Impact of Intermittent Hypoxia on Metabolism and Cognition

Shobatake

Ota

Takahashi

et al. 2022

IJMS

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Intermittent hypoxia (IH), one of the primary pathologies of sleep apnea syndrome (SAS), exposes cells throughout the body to repeated cycles of hypoxia/normoxia that result in oxidative stress and systemic inflammation. Since SAS is epidemiologically strongly correlated with type 2 diabetes/insulin resistance, obesity, hypertension, and dyslipidemia included in metabolic syndrome, the effects of IH on gene expression in the corresponding cells of each organ have been studied intensively to clarify the molecular mechanism of the association between SAS and metabolic syndrome. Dementia has recently been recognized as a serious health problem due to its increasing incidence, and a large body of evidence has shown its strong correlation with SAS and metabolic disorders. In this narrative review, we first outline the effects of IH on the expression of genes related to metabolism in neuronal cells, pancreatic β cells, hepatocytes, adipocytes, myocytes, and renal cells (mainly based on the results of our experiments). Next, we discuss the literature regarding the mechanisms by which metabolic disorders and IH develop dementia to understand how IH directly and indirectly leads to the development of dementia.

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Glial-neuron crosstalk in health and disease: A focus on metabolism, obesity, and cognitive impairment

Cited by 38 publications

References 133 publications

cGAS/STING and innate brain inflammation following acute high-fat feeding

cGAS/STING and innate brain inflammation following acute high-fat feeding

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

The Impact of Intermittent Hypoxia on Metabolism and Cognition

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