Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease

Simpson, Ian A.; Chundu, Koteswara R.; Davies-Hill, Theresa; Honer, William G.; Davies, Peter J.

doi:10.1002/ana.410350507

Cited by 442 publications

(273 citation statements)

References 39 publications

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“…Initial studies by Kalaria and Harik (59) demonstrated a reduction in the 55-kDa form of GLUT1 in cerebral microvessels prepared from Alzheimer's patients compared with normal age-matched controls (60). These observations were confirmed and extended in studies by Simpson et al, who also demonstrated a loss of the 45-kDa glial form of GLUT1 and a striking loss of GLUT3 protein expression in parietal, occipital, and temporal cortex, together with caudate nucleus and hippocampus; only the frontal cortex did not show any significant loss (109). Importantly, the decreases in GLUT3 in the parietal and temporal cortices, hippocampus, and caudate were still significant even after correction for overall neuronal loss using the synaptic protein SNAP25 as a marker.…”

Section: Neuronal Glut3 and Cerebral Glucose Utilizationsupporting

confidence: 77%

The facilitative glucose transporter GLUT3: 20 years of distinction

Simpson

Dwyer

Malide

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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404

322

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Glucose metabolism is vital to most mammalian cells, and the passage of glucose across cell membranes is facilitated by a family of integral membrane transporter proteins, the GLUTs. There are currently 14 members of the SLC2 family of GLUTs, several of which have been the focus of this series of reviews. The subject of the present review is GLUT3, which, as implied by its name, was the third glucose transporter to be cloned (Kayano T, Fukumoto H, Eddy RL, Fan YS, Byers MG, Shows TB, Bell GI. J Biol Chem 263: [15245][15246][15247][15248] 1988) and was originally designated as the neuronal GLUT. The overriding question that drove the early work on GLUT3 was why would neurons need a separate glucose transporter isoform? What is it about GLUT3 that specifically suits the needs of the highly metabolic and oxidative neuron with its high glucose demand? More recently, GLUT3 has been studied in other cell types with quite specific requirements for glucose, including sperm, preimplantation embryos, circulating white blood cells, and an array of carcinoma cell lines. The last are sufficiently varied and numerous to warrant a review of their own and will not be discussed here. However, for each of these cases, the same questions apply. Thus, the objective of this review is to discuss the properties and tissue and cellular localization of GLUT3 as well as the features of expression, function, and regulation that distinguish it from the rest of its family and make it uniquely suited as the mediator of glucose delivery to these specific cells.neurons; sperm; preimplantation embryo; white blood cells GLUCOSE METABOLISM IS VITAL to most mammalian cells, and the passage of glucose across cell membranes is facilitated by a family of integral membrane transporter proteins, the GLUTs. There are currently 14 members of the SLC2 family of GLUTs, several of which have been the focus of this series of reviews. The subject of the present review is GLUT3 which, as implied by its name, was the third glucose transporter to be cloned (62) and was originally designated as the neuronal glucose transporter. Together with GLUT1, -2, and -4, it comprises the Class 1 group of transporters (For review see Refs. 15,81,121). With the cloning of GLUT3, it became apparent that the brain did not rely exclusively on GLUT1 and that GLUT3 was highly and specifically expressed by neurons. Thus, GLUT3 became the third facilitative glucose transporter isoform with unique characteristics suited for cell-specific expression and function. GLUT2 is ideally suited for expression in liver and pancreas due to its high K m for glucose; GLUT4 and its translocation from intracellular vesicles to the cell surface facilitates insulin-stimulated glucose uptake in insulin-sensitive cells: muscle and fat. The overriding question that drove the early work in GLUT3 in the brain was: why would neurons need a separate glucose transporter isoform; what is it about GLUT3 that specifically suits the needs of the highly metabolic and oxidative neuron with its high glucose demand?...

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Section: Neuronal Glut3 and Cerebral Glucose Utilizationsupporting

confidence: 77%

The facilitative glucose transporter GLUT3: 20 years of distinction

Simpson

Dwyer

Malide

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

404

322

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“…Glucose is primarily delivered from the extracellular space into neurons via the insulin‐independent glucose transporter GLUT3, and the insulin‐dependent GLUT4,46, 47 though many other GLUTs contribute. AD is characterized by downregulation of neuronal GLUT3 and glial/endothelial GLUT1, which provides far fewer avenues for glucose uptake into either cell type and thus leads to a reduction in neuronal activity and metabolism 48, 49. Large projection neurons are particularly vulnerable to these metabolic disruptions in AD due to their exceptionally high‐energy requirements coupled with their reliance on GLUT3 for glucose uptake 50, 51.…”

Section: Discussionmentioning

confidence: 99%

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

Mullins

Reiter

Kapogiannis

2018

Ann Clin Transl Neurol

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ObjectiveBrain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case–control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD‐related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.MethodsJ‐modulated Point‐Resolved Spectroscopy (J‐PRESS) and Prior‐Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.Results AD participants showed substantially elevated glucose, lactate, and ascorbate levels compared to older (and younger) controls. In addition, the precuneal glucose elevation discriminated well between AD participants and older controls. Myo‐inositol correlated with CSF p‐Tau181P, total Tau, and the Clinical Dementia Rating (CDR) sum‐of‐boxes score within the AD group.InterpretationHigher glucose to creatine ratios in the AD brain likely reflect lower glucose utilization. Our findings reveal pronounced metabolic abnormalities in the AD brain and strongly suggest that brain glucose merits further investigation as a candidate AD biomarker.

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“…Indeed, rarefaction of cortical capillary beds has recently been reported in Alzheimer's disease (17). Second, Glut-1 expression is decreased in postmortem brain tissue from demented individuals (18)(19)(20). These structural and biochemical abnormalities are likely to contribute to impaired blood flow and the integrity of the physical blood brain barrier, impeding the brain's supply of oxygen, energy, and nutrients, and the removal of toxins from the brain (21).…”

Section: Discussionmentioning

confidence: 99%

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

Troen

Shea‐Budgell²,

Shukitt‐Hale³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

166

133

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In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r ‫؍‬ ؊0.757, P < 0.001), and with plasma total homocysteine (r ‫؍‬ ؊0.631, P ‫؍‬ 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline. cerebrovascular ͉ homocysteine ͉ mouse ͉ nutrition

show abstract

Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease

Cited by 442 publications

References 39 publications

The facilitative glucose transporter GLUT3: 20 years of distinction

The facilitative glucose transporter GLUT3: 20 years of distinction

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

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