Multifunctional role of astrocytes as gatekeepers of neuronal energy supply

Stobart, Jillian; Anderson, Christopher M.

doi:10.3389/fncel.2013.00038

Cited by 208 publications

(184 citation statements)

References 383 publications

(544 reference statements)

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…During heavy synaptic activity, they use up to 80% of their maximal respiratory capacity, and rely on lactate as an additional substrate for OxPhos [70]. Whether neurons produce this lactate themselves or it is 'shuttled' to them by astrocytes is a topic of debate [71]. Despite these controversies, it seems clear that neurons primarily use OxPhos to meet energy demands, are supported metabolically to some degree by astrocytes and are uniquely vulnerable to metabolic exhaustion.…”

Section: Neuronal Energy Metabolism and The Inverse Warburg Effectmentioning

confidence: 99%

Preventing Alzheimer's disease by means of natural selection

Demetrius

Driver

2015

J. R. Soc. Interface.

View full text Add to dashboard Cite

The amyloid cascade model for the origin of sporadic forms of Alzheimer's disease (AD) posits that the imbalance in the production and clearance of beta-amyloid is a necessary condition for the disease. A competing theory called the entropic selection hypothesis asserts that the primary cause of sporadic AD is age-induced mitochondrial dysregulation and the following cascade of events: (i) metabolic reprogramming-the upregulation of oxidative phosphorylation in compensation for insufficient energy production in neurons, (ii) natural selection-competition between intact and reprogrammed neurons for energy substrates and (iii) propagation-the spread of the disease due to the selective advantage of neurons with upregulated metabolism. Experimental studies to evaluate the predictions of the amyloid cascade model are being continually retuned to accommodate conflicts of the predictions with empirical data. Clinical trials of treatments for AD based on anti-amyloid therapy have been unsuccessful. We contend that these anomalies and failures stem from a fundamental deficit of the amyloid hypothesis: the model derives from a nuclear-genomic perspective of sporadic AD and discounts the bioenergetic processes that characterize the progression of most age-related disorders. In this article, we review the anomalies of the amyloid model and the theoretical and empirical support for the entropic selection theory. We also discuss the new therapeutic strategies based on natural selection which the model proposes.

show abstract

Section: Neuronal Energy Metabolism and The Inverse Warburg Effectmentioning

confidence: 99%

Preventing Alzheimer's disease by means of natural selection

Demetrius

Driver

2015

J. R. Soc. Interface.

View full text Add to dashboard Cite

show abstract

“…Details of astrocyte CNS activity have been described in several excellent reviews. [1][2][3] For example, astrocytes produce lactate from glucose to feed to neurons as their energy source utilizing astrocytic monocarboxylate transporter 1 (MCT1) and MCT4 (export), and neuronal MCT2 (uptake), respectively. This is the so-called lactate shuttle.…”

Section: Introductionmentioning

confidence: 99%

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Furihata

Anzai

2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

It has become widely acknowledged that astrocytes play essential roles in maintaining physiological central nervous system (CNS) activities. Astrocytes fulfill their roles partly through the manipulation of their plasma membrane transporter functions, and therefore these transporters have been regarded as promising drug targets for various CNS diseases. A representative example is excitatory amino acid transporter 2 (EAAT2), which works as a critical regulator of excitatory signal transduction through its glutamate uptake activity at the tripartite synapse. Thus, enhancement of EAAT2 functionality is expected to accelerate glutamate clearance at synapses, which is a promising approach for the prevention of over-excitation of glutamate receptors. In addition to such well-known astrocyte-specific transporters, cumulative evidence suggests that multi-specific organic ion transporters (i.e., organic cation/anion transporters [OCTs/OATs], carnitine/organic cation transporters [OCTNs], and organic anion transporting polypeptides [OATPs]) are also functionally expressed in astrocytes. Even though identification and characterization of their physiological/pathophysiological roles in astrocytes are in the initial stage, the findings obtained so far indicate that OCT3 and plasma membrane monoamine transporter are significantly involved in the clearance of biogenic amine neurotransmitters in the synaptic cleft, and that OCTN2 and OATP1C1 provide a cellular entry gate for carnitine/acetyl-L-carnitine and thyroxine, respectively. Therefore, organic ion transporters, including those mentioned above, are expected to become emerging pharmacological targets for various CNS diseases. With such expectations in mind, this review will briefly summarize the functional expression of organic ion transporters in astrocytes.

show abstract

“…One of the main functions of GLAST is to detoxify the synaptic area of neurons conducting glutaminergic transmission (for review see ref. [Stobart and Anderson, 2013]). This is done by the astrocyte taking up excess glutamic acid via GLAST.…”

Section: Discussionmentioning

confidence: 99%

Anaplerotic Accumulation of Tricarboxylic Acid Cycle Intermediates as Well as Changes in Other Key Metabolites During Heterotopic Ossification

Davis

Salisbury

Olmsted-Davis

et al. 2015

J of Cellular Biochemistry

View full text Add to dashboard Cite

Heterotopic ossification (HO) is the de novo formation of bone that occurs in soft tissue, through recruitment, expansion, and differentiation of multiple cells types including transient brown adipocytes, osteoblasts, chondrocytes, mast cells, and platelets to name a few. Much evidence is accumulating that suggests changes in metabolism may be required to accomplish this bone formation. Recent work using a mouse model of heterotopic bone formation reliant on delivery of adenovirus‐transduced cells expressing low levels of BMP2 showed the immediate expansion of a unique brown adipocyte‐like cell. These cells are undergoing robust uncoupled oxidative phosphorylation to a level such that oxygen in the microenvironment is dramatically lowered creating areas of hypoxia. It is unclear how these oxygen changes ultimately affect metabolism and bone formation. To identify the processes and changes occurring over the course of bone formation, HO was established in the mice, and tissues isolated at early and late times were subjected to a global metabolomic screen. Results show that there are significant changes in both glucose levels, as well as TCA cycle intermediates. Additionally, metabolites necessary for oxidation of stored lipids were also found to be significantly elevated. The complete results of this screen are presented here, and provide a unique picture of the metabolic changes occurring during heterotopic bone formation. J. Cell. Biochem. 117: 1044–1053, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.

show abstract

Multifunctional role of astrocytes as gatekeepers of neuronal energy supply

Cited by 208 publications

References 383 publications

Preventing Alzheimer's disease by means of natural selection

Preventing Alzheimer's disease by means of natural selection

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Anaplerotic Accumulation of Tricarboxylic Acid Cycle Intermediates as Well as Changes in Other Key Metabolites During Heterotopic Ossification

Contact Info

Product

Resources

About