Immunogold cytochemistry of the blood–brain barrier glucose transporter GLUT1 and endogenous albumin in the developing human brain

Virgintino, Daniela; Robertson, David; Benagiano, Vincenzo; Errede, Mariella; Bertossi, M; Ambrosi, G; Roncali, Luisa

doi:10.1016/s0165-3806(00)00086-9

Cited by 42 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, GLUT1 is much more densely expressed in human cerebral capillaries from the 12th to the 18th postconceptional week and predominantly redistributed to the abluminal endothelial surface during that period, whereas the neuropil does not appear to parallel this increase in expression. 20 The abundance of transporters other than Glut1 therefore may provide an explanation of our finding of regionality. Several, although not entirely applicable here, experimental pathological findings in animals and humans who suffered acute and severe hypoglycemia 21 confirm the vulnerability of all the cerebral structures affected in our patients (ie, cortex, thalamus).…”

Section: Discussionmentioning

confidence: 86%

Imaging the metabolic footprint of Glut1 deficiency on the brain

Pascual

Heertum

Wang

et al. 2002

Annals of Neurology

137

100

View full text Add to dashboard Cite

Cerebral 18F-fluorodeoxyglucose positron emission tomography in 14 patients with microcephaly, developmental delay, seizures, and mutations of the glucose transporter Glut1 (Glut1 deficiency syndrome) showed distinct abnormalities. Within a global context of diminished cortical uptake, more severe hypometabolism was found in the mesial temporal regions and thalami, accentuating a relative signal increase in the basal ganglia. In contrast, the structure of the brain appeared preserved in patients additionally investigated by magnetic resonance imaging. This metabolic footprint was relatively constant in all patients regardless of age, seizure history, or therapies and therefore constitutes a radiological signature of the disease. The full expression of the signature in the youngest patient (aged 19 months) indicates that the state of haploinsufficiency caused by Glut1 mutation leaves a permanent footprint on the nervous system from its earlier postnatal stages of development. The potential benefit of prompt diagnosis, aided by 18F-fluorodeoxyglucose positron emission tomography, and early initiation of available therapies is underscored by our results.

show abstract

Section: Discussionmentioning

confidence: 86%

Imaging the metabolic footprint of Glut1 deficiency on the brain

Pascual

Heertum

Wang

et al. 2002

Annals of Neurology

137

100

View full text Add to dashboard Cite

show abstract

“…Our previous studies, in agreement with the few reports carried out in human and other species (Saunders 1977;Dziegielewska et al 1979;Møllgård and Saunders 1986;Bauer et al 1993Bauer et al , 1995, corroborate the concept of a precocious 'working attitude' of the human fetal BBB. During human telencephalon development, the endothelial cells express high levels of GLUT-1 (glucose transporter isoform 1) with an adult-like asymmetrical distribution on the opposite endothelial membranes (Virgintino et al 1998a(Virgintino et al , 2000, a subcellular localization that seems to be regulated by a fence function of the TJs (Gerhart et al 1989;Dobrogowska and Vorbrodt 1999;Lippoldt et al 2000b) and that temporally corresponds to the presence of an endothelial barrier to endogenous serum albumin (Virgintino et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Immunolocalization of tight junction proteins in the adult and developing human brain

Virgintino

Errede

Robertson

et al. 2004

Histochem Cell Biol

Self Cite

127

112

View full text Add to dashboard Cite

The formation of endothelial tight junctions (TJs) is crucial in blood-brain barrier (BBB) differentiation, and the expression and targeting of TJ-associated proteins mark the beginning of BBB functions. Using confocal microscopy, this study analyzed endothelial TJs in adult human cerebral cortex and the fetal telencephalon and leptomeninges in order to compare the localization of two TJ-associated transmembrane proteins, occludin and claudin-5. In the arterioles and microvessels of adult brain, occludin and claudin-5 form continuous bands of endothelial immunoreactivity. During fetal development, occludin and claudin-5 immunoreactivity is first detected as a diffuse labeling of endothelial cytoplasm. Later, at 14 weeks, the immunosignal for both proteins shifts from the cytoplasm to the interface of adjacent endothelial cells, forming a linear, widely discontinuous pattern of immunoreactivity that achieves an adult-like appearance within a few weeks. These results demonstrate that occludin and claudin-5 expression is an early event in human brain development, followed shortly by assembly of both proteins at the junctional areas. This incremental process suggests more rapid establishment of the human BBB, consistent with its specific function of creating a suitable environment for neuron differentiation and neurite outgrowth during neocortical histogenesis.

show abstract

“…GLUT1, the prototypic member of this protein family, is highly expressed in erythrocytes and the central nervous system and is believed to play an essential role in the homeostasis of brain glucose in the developing human infant (2). In support of this concept, infants with GLUT1 deficiency syndrome, a rare genetic disorder resulting from inherited heterozygous loss-of-function mutations in the gene encoding GLUT1, develop seizures, acquired microcephaly and profound developmental delay in association with profound hypoglycorrhachia (3).…”

mentioning

confidence: 99%

GLUT1 Deficiency Links Nutrient Availability and Apoptosis during Embryonic Development

Jensen

Gitlin

Carayannopoulos

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

GLUT1 is essential for human brain development and function, as evidenced by the severe epileptic encephalopathy observed in children with GLUT1 deficiency syndrome resulting from inherited loss-of-function mutations in the gene encoding this facilitative glucose transporter. To further elucidate the pathophysiology of this disorder, the zebrafish orthologue of human GLUT1 was identified, and expression of this gene was abrogated during early embryonic development, resulting in a phenotype of aberrant brain organogenesis consistent with the observed expression of Glut1 in the embryonic tectum and specifically rescued by human GLUT1 mRNA. Affected embryos displayed impaired glucose uptake concomitant with increased neural cell apoptosis and subsequent ventricle enlargement, trigeminal ganglion cell loss, and abnormal hindbrain architecture. Strikingly, inhibiting expression of the zebrafish orthologue of the proapoptotic protein Bad resulted in complete rescue of this phenotype, and this occurred even in the absence of restoration of apparent glucose uptake. Taken together, these studies describe a tractable system for elucidating the cellular and molecular mechanisms of Glut1 deficiency and provide compelling in vivo genetic evidence directly linking nutrient availability and activation of mitochondria-dependent apoptotic mechanisms during embryonic brain development.The cellular uptake of glucose is dependent in part upon the GLUT family of polytopic membrane transporters that facilitate the passive diffusion of this essential nutrient across membranes (1). GLUT1, the prototypic member of this protein family, is highly expressed in erythrocytes and the central nervous system and is believed to play an essential role in the homeostasis of brain glucose in the developing human infant (2). In support of this concept, infants with GLUT1 deficiency syndrome, a rare genetic disorder resulting from inherited heterozygous loss-of-function mutations in the gene encoding GLUT1, develop seizures, acquired microcephaly and profound developmental delay in association with profound hypoglycorrhachia (3). Despite considerable study of these patients, the neurochemical and neuropathologic consequences of GLUT1 deficiency during development are not well understood, and treatment of affected patients remains challenging.Although abundant in the extracellular milieu, the cellular uptake of glucose is precisely regulated by specific growth factors and signaling pathways (4). Cell culture studies reveal that inhibition of cellular glucose uptake dramatically increases apoptosis under conditions of growth factor restriction and that cell survival under such circumstances is dependent upon the regulation of glucose uptake and metabolism by the proto-oncogene Akt (5-7). A biochemical link between glucose homeostasis and apoptosis was further suggested by studies demonstrating an interaction between the proapoptotic protein, Bad, and the glycolytic enzyme, glucokinase (8). In support of these findings, a recent study now demonstrates a...

show abstract

Immunogold cytochemistry of the blood–brain barrier glucose transporter GLUT1 and endogenous albumin in the developing human brain

Cited by 42 publications

References 20 publications

Imaging the metabolic footprint of Glut1 deficiency on the brain

Imaging the metabolic footprint of Glut1 deficiency on the brain

Immunolocalization of tight junction proteins in the adult and developing human brain

GLUT1 Deficiency Links Nutrient Availability and Apoptosis during Embryonic Development

Contact Info

Product

Resources

About