GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration

Winkler, Ethan A.; Nishida, Yoichiro; Sagare, Abhay P.; Rege, Sanket; Bell, Robert D.; Perlmutter, David D.; Sengillo, Jesse D.; Hillman, Sara; Kong, Pan; Nelson, Amy R.; Sullivan, John S.; Zhao, Zhen; Meiselman, Herbert J.; Wenby, R.B.; Soto, Jamie; Abel, E. Dale; Makshanoff, Jacob; Zúñiga, Edward; Vivo, Darryl C. De; Zloković, Berislav V.

doi:10.1038/nn.3966

Cited by 549 publications

(550 citation statements)

References 61 publications

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“…Recent work suggests that contribution of astrocytic glucose transporters is less significant than the importance of the vascular endothelial transporters (107). Further work also suggests that glial glucose transporters might not provide an appropriate target for preventing AD: as in drosophila AD models overexpression of GLUT1 in glia had no effect against Aβ induced neurotoxicity (108).…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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“…It has been reported that various peripheral pathologies that affect glucose levels lead to alterations in brain functions, including functions related to neuronal plasticity, memory, and learning (22,49). In Drosophila, it has been described that increase of the glucose transport induces a decrease in the neuronal damage induced by amyloid ␤ (50).…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

“…In brain tissue, glucose is oxidized through glycolysis and oxidative phosphorylation to produce ATP, most of which is consumed by neurons during the recovery of ion gradients after synaptic transmission (19,20). In several models of neurological disorders, it has been shown that dysfunctional glucose utilization is a critical step in the onset and progression of disease (21,22). Accordingly, enhancing glucose utilization in vivo induces significant improvements in cognitive functions, such as memory and learning (23)(24)(25).…”

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confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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“…These are designed to lower plasma glucose by promoting glycosuria, but there are encouraging signs that they may also have renoprotective effects, perhaps by lowering the elevated glucose concentrations in the proximal tubular cell, as well as having other relevant actions, including blood pressure reduction and weight loss. Tissue selectivity would be a prerequisite for any attempt to modulate tissue glucose uptake in humans because reduced blood-brain barrier glucose flux via GLUT1 is implicated in the development of neurodegenerative conditions such as Alzheimer's disease [18].…”

Section: What Might the Future Hold?mentioning

confidence: 99%

50 years forward: mechanisms of hyperglycaemia-driven diabetic complications

Russell

Cooper

2015

Diabetologia

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The advent of insulin treatment in 1923 meant fewer diabetes deaths from acute metabolic deterioration and sepsis and a progressive increase in the burden of disease caused by end-organ damage. These diabetic complications are the major cause of morbidity and premature mortality among diabetic subjects. Over the last 50 years it has become apparent that diabetic complications in disparate tissues may result from a combination of common pathological processes. Pathways activated by initial metabolic insults are promoted by co-factors such as renin-angiotensin-aldosterone system activation, hyperinsulinaemia, underlying genetic susceptibility, and traditional vascular risk factors, particularly hypertension and lipids. These common pathways include AGE formation, reactive oxygen species overproduction, protein kinase C activation, mitochondrial dysfunction and activation of proinflammatory and profibrotic signalling cascades.

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GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration

Cited by 549 publications

References 61 publications

Astrocytic transporters in Alzheimer's disease

Astrocytic transporters in Alzheimer's disease

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

50 years forward: mechanisms of hyperglycaemia-driven diabetic complications

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