Brain glucose transporter protein 2 and sporadic Alzheimer’s disease

Šalković‐Petrišić, Melita; Riederer, Peter

doi:10.2478/v10134-010-0030-y

Cited by 10 publications

(8 citation statements)

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“…This observation was consistent with another study published earlier ( Paidi et al., 2015 ). Further, when given systemically STZ acts as a diabetogenic agent and destroys β cells of the pancreas after gaining entry in to the cells through GLUT2 transporters ( Grieb, 2016 ; Šalković-Petrišić and Riederer, 2010 -). In brain GLUT2 transporters are present in certain areas including hypothalamus where these are located in neurons, endothelial cells as well as special type of ependymal cells called tanycytes ( Elizondo-Vega et al., 2015 ; García et al, 2003 ; Thorens, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, it will be interesting to probe if other toxic effects of ICV-STZ administration on brain reported in the literature such as oxidative stress, decreased cerebral glucose utilization and neuroinflammation also differ in GR 1 and GR 2 rats. The mechanisms of the multiple toxic effects of STZ on brain after ICV administration are largely unknown, but the damage to GLUT2 containing cells in the brain by STZ could play an important role in this process ( Grieb, 2016 ; Knezovic et al., 2017 ; Šalković-Petrišić and Riederer, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…and neuroinflammation also differ in GR 1 and GR 2 rats. The mechanisms of the multiple toxic effects of STZ on brain after ICV administration are largely unknown, but the damage to GLUT2 containing cells in the brain by STZ could play an important role in this process (Grieb, 2016;Knezovic et al, 2017;Salkovi c-Petri si c and Riederer, 2010). It is also interesting to note in the context of our results that moderate inhibition of complex I-III activity has been shown to increase the neuronal AMP content and activation of AMP dependent protein kinase (AMPK) which causes improved bioenergetic performance of mitochondria and reprogramming of neuronal metabolism (Du et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight

Poddar

Singh²,

Kumar³

et al. 2020

Heliyon

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The effects of streptozotocin (STZ) on the brain after intracerebroventricular (ICV) administration in rodents have been suggested to mimic the pathogenesis of sporadic Alzheimer's disease (AD). Oxidative damage, decreased glucose utilization, mitochondrial bioenergetic changes, neuroinflammation and behavioral impairment have been reported in rodents after ICV-STZ administration. However, the molecular mechanisms of STZ effects on brain after ICV administration remain highly controversial. In this study we re-examined several bioenergetic parameters of rat brain mitochondria on day 15 following ICV-STZ treatment. We observed only a moderate but statistically significant decrease in complex I-III activity in brain mitochondria from streptozotocin-treated rats. There were no changes in complex II-III activity or phosphorylation capacity of brain mitochondria after streptozotocin treatment. More importantly, it was observed that ICV-STZ treatment caused variable degrees of body-weight loss in rats, and complex I-III activity was decreased only in those rats showing a significant (more than 10%–35%) loss in body-weights.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight

Poddar

Singh²,

Kumar³

et al. 2020

Heliyon

View full text Add to dashboard Cite

show abstract

“…Thus, along with mitochondrial oxidative phosphorylation, MAO activity is probably the second most significant source of reactive oxygen species (ROS) and oxidative stress in the brain (Edmondson et al, 2014). Another unfavourable consequence of MAO activity, the production of ammonia, puts additional strain on the NH 4+ -clearing system of monoaminergic neurons making them more vulnerable, because it involves glutamate transporters (Šalković-Petrišić and Riederer, 2010), glutamate dehydrogenase 1 (GLUD1) and glutamine synthetase (also glutamate ammonia ligase, GLUL), which decrease the 2-oxoglutarate (2OG) and glutamate pools. Neurons are very sensitive to the depletion of these pools, especially 2OG, because it decreases adenosine triphosphate (ATP) production in the citric acid cycle.…”

Section: Chemical Neuroanatomy Of the Monoaminergic Systemsmentioning

confidence: 99%

Monoaminergic neuropathology in Alzheimer’s disease

Šimić

Leko

Wray³

et al. 2017

Progress in Neurobiology

233

142

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None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

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“…Involvement of GLUT2 as mediator of icv STZ effects has been postulated [ 83 , 94 , 95 ]. GLUT2 is the isoform present in pancreatic insulin producing cells and also involved in glucose sensing.…”

Section: Does Icv Stz Cause Brain Insulin Receptors Desensitization Dmentioning

confidence: 99%

Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer’s Disease: in Search of a Relevant Mechanism

2015

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Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer’s disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer’s brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer’s disease.

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Brain glucose transporter protein 2 and sporadic Alzheimer’s disease

Cited by 10 publications

References 69 publications

Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight

Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight

Monoaminergic neuropathology in Alzheimer’s disease

Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer’s Disease: in Search of a Relevant Mechanism

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