CoChat
Sign Up
Cited by 171Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchBarrier Structure and Function Studies

A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

Open access
Kyrtata, Natalia, Emsley, Hedley C. A., Sparasci, Oli, Parkes, Laura M., Dickie, Ben R.·2021·Frontiers in Neuroscience
DOI 10.3389/fnins.2021.626636PMC PMC8173065
Open this paper in CoChat — free accountOpen PDF

Abstract

Introduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnins.2021.626636

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inflammatory cytokines IL-1β and TNF-α, abundant in the AD brain, suppress GLUT expression, while oxidative stress further destabilizes and inactivates transporter proteins.

    “Furthermore, inflammatory cytokines such as IL-1β and tumor necrosis factor alpha (TNF-α), abundant in the AD brain, suppress GLUT expression, while oxidative stress further destabilizes and inactivates transporter proteins.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [72]

    The Discussion (page not provided) reports that Aβ impaired glucose transport in cultured rat neurons through a mechanism involving membrane lipid peroxidation. That lends limited support to an oxidative mechanism, but the review does not say oxidative stress destabilizes or inactivates transporter proteins. Searches for IL-1β and TNF-α found no passage saying those cytokines are abundant in AD brain or suppress GLUT expression. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 104

  1. Abdul Muneer P. M. Alikunju S. Szlachetka A. M. Murrin L. C. Haorah J. (2011). Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol. Neurodegener. 6: 23. 10.1186/1750-1326-6-23 21426580 PMC3073895 · DOI
  2. Ahn K. C. Learman C. R. Dunbar G. L. Maiti P. Jang W. C. Cha H. C.. (2018). Characterization of impaired cerebrovascular structure in APP/PS1 mouse brains. Neuroscience 385, 246– 254. 10.1016/j.neuroscience.2018.05.002 29777753 · DOI
  3. An Y. Varma V. R. Varma S. Casanova R. Dammer E. Pletnikova O.. (2018). Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimer's Dement. 14, 318– 329. 10.1016/j.jalz.2017.09.011 29055815 PMC5866736 · DOI
  4. Biswas J. Gupta S. Verma D. K. Gupta P. Singh A. Tiwari S.. (2018). Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology. Cell. Signal 42, 211– 226. 10.1016/j.cellsig.2017.10.018 29126976 · DOI
  5. Bokde A. L. W. Pietrini P. Ibáñez V. Furey M. L. Alexander G. E. Graff-Radford N. R.. (2001). The effect of brain atrophy on cerebral hypometabolism in the visual variant of Alzheimer disease. Arch. Neurol. 58, 480– 486. 10.1001/archneur.58.3.480 11255453 · DOI
  6. Burke M. J. C. Nelson L. Slade J. Y. Oakley A. E. Khundakar A. A. Kalaria R. N. (2014). Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias. Neuropathol. Appl. Neurobiol. 40, 284– 295. 10.1111/nan.12085 24003901 PMC4282329 · DOI
  7. Carruthers A. Helgerson A. L. (1991). Inhibitions of sugar transport produced by ligands binding at opposite sides of the membrane. evidence for simultaneous occupation of the carrier by maltose and cytochalasin B. Biochemistry 30, 3907– 3915. 10.1021/bi00230a015 2018762 · DOI
  8. Castello M. A. Soriano S. (2014). On the origin of Alzheimer's disease. trials and tribulations of the amyloid hypothesis. Ageing Res. Rev. 13, 10– 12. 10.1016/j.arr.2013.10.001 24252390 · DOI
  9. Chen Z. Zhong C. (2013). Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies. Prog. Neurobiol. 108, 21– 43. 10.1016/j.pneurobio.2013.06.004 23850509 · DOI
  10. Chua L. M. Lim M. L. Chong P. R. Hu Z. P. Cheung N. S. Wong B. S. (2012). Impaired neuronal insulin signaling precedes Aβ42 accumulation in female AβPPsw/PS1ΔE9 Mice. J. Alzheimer's Dis. 29, 783– 791. 10.3233/JAD-2012-111880 22337827 · DOI
  11. Cohen S. S. Powers B. R. Lerch-Gaggl A. Teng R.-J. Konduri G. G. (2014). Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension. Int. J. Dev. Neurosci. 38, 113– 118. 10.1016/j.ijdevneu.2014.08.003 25172169 PMC4267966 · DOI
  12. De Leon M. J. Convit A. Wolf O. T. Tarshish C. Y. DeSanti S. Rusinek H.. (2001). Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc. Natl. Acad. Sci. U.S.A. 98, 10966– 10971. 10.1073/pnas.191044198 11526211 PMC58582 · DOI · Paper page
  13. de Leon M. J. Ferris S. H. George A. E. Christman D. R. Fowler J. S. Gentes C.. (1983). Positron emission tomographic studies of aging and Alzheimer disease. AJNR. Am. J. Neuroradiol. 4, 568– 571. 6410799 PMC8334899
  14. Deng Y. Li B. Liu Y. Iqbal K. Grundke-Iqbal I. Gong C. X. (2009). Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer's disease. Am. J. Pathol. 175, 2089– 2098. 10.2353/ajpath.2009.090157 19815707 PMC2774072 · DOI
  15. Ding F. Yao J. Rettberg J. R. Chen S. Brinton R. D. (2013). Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: Implication for bioenergetic intervention. PLoS ONE 8: e79977. 10.1371/journal.pone.0079977 24244584 PMC3823655 · DOI
  16. Do T. M. Alata W. Dodacki A. Traversy M. T. Chacun H. Pradier L.. (2014). Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer's disease. Neuropharmacology 81, 311– 317. 10.1016/j.neuropharm.2014.02.010 24631967 · DOI
  17. Fong C. W. (2015). Permeability of the blood–brain barrier: molecular mechanism of transport of drugs and physiologically important compounds. J. Membr. Biol. 248, 651– 669. 10.1007/s00232-015-9778-9 25675910 · DOI
  18. Friedland R. P. Jagust W. J. Huesman R. H. Koss E. Knittel B. Mathis C. A.. (1989). Regional cerebral glucose transport and utilization in Alzheimer's disease. Neurology 39, 1427– 1434. 10.1212/WNL.39.11.1427 2812318 · DOI
  19. Gejl M. Brock B. Egefjord L. Vang K. Rungby J. Gjedde A. (2017). Blood-brain glucose transfer in Alzheimer's disease: effect of GLP-1 analog treatment. Sci. Rep. 7: 17490. 10.1038/s41598-017-17718-y 29235507 PMC5727512 · DOI · Paper page
  20. Gejl M. Gjedde A. Egefjord L. Møller A. Hansen S. Vang K.. (2016). In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front. Aging Neurosci. 8: 108. 10.3389/fnagi.2016.00108 27252647 PMC4877513 · DOI · Paper page
  21. Gil-Iturbe E. Solas M. Cuadrado-Tejedo M. García-Osta A. Escoté X. Ramírez M. J.. (2020). GLUT12 expression in brain of mouse models of Alzheimer's Disease. Mol. Neurobiol. 57, 798– 805. 10.1007/s12035-019-01743-1 31473905 · DOI
  22. Griffith C. M. MacKlin L. N. Cai Y. Sharp A. A. Yan X. X. Reagan L. P.. (2019). Impaired glucose tolerance and reduced plasma insulin precede decreased AKT phosphorylation and GLUT3 translocation in the hippocampus of Old 3xTg-AD Mice. J. Alzheimer's Dis. 68, 809– 837. 10.3233/JAD-180707 30775979 · DOI
  23. Grundke-Iqbal I. Iqbal K. Tung Y. C. Quinlan M. Wisniewski H. M. Binder L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913– 4917. 10.1073/pnas.83.13.4913 3088567 PMC323854 · DOI · Paper page
  24. Gu J. Jin N. Ma D. Chu D. Iqbal K. Gong C. X.. (2018). Calpain I activation causes GLUT3 proteolysis and downregulation of O-GlcNAcylation in Alzheimer's disease brain. J. Alzheimer's Dis. 62, 1737– 1746. 10.3233/JAD-171047 29614685 · DOI
  25. Hanseeuw B. J. Betensky R. A. Jacobs H. I. L. Schultz A. P. Sepulcre J. Becker J. A.. (2019). Association of amyloid and tau with cognition in preclinical Alzheimer disease. JAMA Neurol. 76, 915– 924. 10.1001/jamaneurol.2019.1424 31157827 PMC6547132 · DOI · Paper page
  26. Harik S. I. (1992). Changes in the glucose transporter of brain capillaries. Can. J. Physiol. Pharmacol. 70, S113– S117. 10.1139/y92-252 1295661 · DOI
  27. Harik S. I. Kalaria R. N. (1991). Blood-brain barrier abnormalities in Alzheimer's diseasea. Ann. N. Y. Acad. Sci. 640, 47– 52. 10.1111/j.1749-6632.1991.tb00189.x 1685645 · DOI
  28. Harr S. D. Simonian N. A. Hyman B. T. (1995). Functional alterations in Alzheimer's disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J. Neuropathol. Exp. Neurol. 54, 38– 41. 10.1097/00005072-199501000-00005 7815078 · DOI
  29. Hase Y. Ding R. Harrison G. Hawthorne E. King A. Gettings S.. (2019). White matter capillaries in vascular and neurodegenerative dementias. Acta Neuropathol. Commun. 7: 16. 10.1186/s40478-019-0666-x 30732655 PMC6366070 · DOI · Paper page
  30. Hernandez-Garzón E. Fernandez A. M. Perez-Alvarez A. Genis L. Bascuñana P. Fernandez de la Rosa R.. (2016). The insulin-like growth factor I receptor regulates glucose transport by astrocytes. Glia 64, 1962– 1971. 10.1002/glia.23035 27462832 · DOI
  31. Honer W. G. Dickson D. W. Gleeson J. Davies P. (1992). Regional synaptic pathology in Alzheimer's disease. Neurobiol. Aging 13, 375– 382. 10.1016/0197-4580(92)90111-A 1625766 · DOI · Paper page
  32. Hooijmans C. R. Graven C. Dederen P. J. Tanila H. van Groen T. Kiliaan A. J. (2007). Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res. 1181, 93– 103. 10.1016/j.brainres.2007.08.063 17916337 · DOI
  33. Horwood N. Davies D. C. (1994). Immunolabelling of hippocampal microvessel glucose transporter protein is reduced in Alzheimer's disease. Virchows Arch. 425, 69– 72. 10.1007/BF00193951 7921416 · DOI · Paper page
  34. Iadecola C. (2015). Sugar and Alzheimer's disease: a bittersweet truth. Nat. Neurosci. 18, 477– 478. 10.1038/nn.3986 25811474 PMC4731873 · DOI
  35. Jagust W. Gitcho A. Sun F. Kuczynski B. Mungas D. Haan M. (2006). Brain imaging evidence of preclinical Alzheimer's disease in normal aging. Ann. Neurol. 59, 673– 681. 10.1002/ana.20799 16470518 · DOI · Paper page
  36. Jagust W. J. Seab P. J. Huesman R. H. Valk P. E. Mathis C. A. Reed B. R.. (1991). Diminished glucose transport in Alzheimer's disease: dynamic PET studies. J. Cereb. Blood Flow Metab. 11, 323– 330. 10.1038/jcbfm.1991.65 1997504 · DOI
  37. Jin N. Qian W. Yin X. Zhang L. Iqbal K. Grundke-Iqbal I.. (2013). CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer's disease. Nucleic Acids Res. 41, 3240– 3256. 10.1093/nar/gks1227 23341039 PMC3597642 · DOI
  38. Kalaria R. N. Harik S. I. (1989). Abnormalities of the glucose transporter at the blood-brain barrier and in brain in Alzheimer's disease. Prog. Clin. Biol. Res. 317, 415– 421. 2602426
  39. Kametani F. Hasegawa M. (2018). Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer's disease. Front. Neurosci. 12: 25. 10.3389/fnins.2018.00025 29440986 PMC5797629 · DOI · Paper page
  40. Kawai M. Kalaria R. N. Harik S. I. Perry G. (1990). The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease. Am. J. Pathol. 137, 1435– 1446. 2260630 PMC1877722
  41. Kimura Y. Naganawa M. (2005). “Imaging detailed glucose metabolism in the brain using MAP estimation in positron emission tomography,” in Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings (Shanghai: Institute of Electrical and Electronics Engineers Inc.), 4477– 4479. 10.1109/IEMBS.2005.1615461 17281231 · DOI
  42. Knezovic A. Loncar A. Homolak J. Smailovic U. Osmanovic Barilar J. Ganoci L.. (2017). Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer's disease? J. Neural Transm. 124, 695– 708. 10.1007/s00702-017-1727-6 28470423 · DOI
  43. Koepsell H. (2020). Glucose transporters in brain in health and disease. Pflugers Arch. Eur. J. Physiol. 472, 1299– 1343. 10.1007/s00424-020-02441-x 32789766 PMC7462931 · DOI · Paper page
  44. Kosik K. S. Joachim C. L. Selkoe D. J. (1986). Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 83, 4044– 4048. 10.1073/pnas.83.11.4044 2424016 PMC323662 · DOI
  45. Kouznetsova E. Klingner M. Sorger D. Sabri O. Großmann U. Steinbach J.. (2006). Developmental and amyloid plaque-related changes in cerebral cortical capillaries in transgenic Tg2576 Alzheimer mice. Int. J. Dev. Neurosci. 24, 187– 193. 10.1016/j.ijdevneu.2005.11.011 16423498 · DOI
  46. Kumagai A. K. Kang Y. S. Boado R. J. Pardridge W. M. (1995). Upregulation of blood-brain barrier GLUT1 glucose transporter protein and mRNA in experimental chronic hypoglycemia. Diabetes 44, 1399– 1404. 10.2337/diab.44.12.1399 7589845 · DOI
  47. Kumari U. Heese K. (2010). Cardiovascular dementia - a different perspective. Open Biochem. J. 4, 29– 52. 10.2174/1874091X01004010029 20448820 PMC2864432 · DOI
  48. Kuznetsova E. Schliebs R. (2013). β-Amyloid, cholinergic transmission, and cerebrovascular system - a developmental study in a mouse model of Alzheimer's disease. Curr. Pharm. Des. 19, 6749– 6765. 10.2174/13816128113199990711 23530514 · DOI
  49. Larrabee M. G. (2002). Lactate metabolism and its effects on glucose metabolism in an excised neural tissue. J. Neurochem. 64, 1734– 1741. 10.1046/j.1471-4159.1995.64041734.x 7891102 · DOI
  50. Lee Y. J. Kim J. E. Hwang I. S. Kwak M. H. Lee J. H. Jung Y. J.. (2013). Alzheimer's phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism. Mol. Med. Rep. 7, 1571– 1578. 10.3892/mmr.2013.1404 23546527 · DOI
  51. Leen W. G. Klepper J. Verbeek M. M. Leferink M. Hofste T. van Engelen B. G.. (2010). Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain J. Neurol. 133, 655– 670. 10.1093/brain/awp336 20129935 · DOI
  52. Leen W. G. Taher M. Verbeek M. M. Kamsteeg E. J. van de Warrenburg B. P. Willemsen M. A. (2014). GLUT1 deficiency syndrome into adulthood: a follow-up study. J. Neurol. 261, 589– 599. 10.1007/s00415-014-7240-z 24413642 · DOI
  53. Leloup C. Arluison M. Kassis N. Lepetit N. Cartier N. Ferré P.. (1996). Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Mol. Brain Res. 38, 45– 53. 10.1016/0169-328X(95)00306-D 8737666 · DOI
  54. Liu Y. Liu F. Grundke-Iqbal I. Iqbal K. Gong C.-X. (2009). Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J. Neurochem. 111, 242– 249. 10.1111/j.1471-4159.2009.06320.x 19659459 PMC2760012 · DOI
  55. Liu Y. Liu F. Iqbal K. Grundke-Iqbal I. Gong C. X. (2008). Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett. 582, 359– 364. 10.1016/j.febslet.2007.12.035 18174027 PMC2247364 · DOI
  56. Lund-Andersen H. (1979). Transport of glucose from blood to brain. Physiol. Rev. 59, 305– 352. 10.1152/physrev.1979.59.2.305 375257 · DOI
  57. Magistretti P. J. Pellerin L. (1999). Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 1155– 1163. 10.1098/rstb.1999.0471 10466143 PMC1692634 · DOI
  58. Mark R. J. Pang Z. Geddes J. W. Uchida K. Mattson M. P. (1997). Amyloid β-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046– 1054. 10.1523/JNEUROSCI.17-03-01046.1997 8994059 PMC6573165 · DOI · Paper page
  59. Masdeu J. C. (2008). Neuroimaging of disorders leading to dementia. Contin. Lifelong Learn. Neurol. 14, 144– 163. 10.1212/01.CON.0000333204.72795.ed 18957178 · DOI
  60. Masliah E. Hansen L. Albright T. Mallory M. Terry R. D. (1991). Immunoelectron microscopic study of synaptic pathology in Alzheimer's disease. Acta Neuropathol. 81, 428– 433. 10.1007/BF00293464 1903014 · DOI
  61. Masliah E. Terry R. D. Alford M. DeTeresa R. (1990). Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections. J. Histochem. Cytochem. 38, 837– 844. 10.1177/38.6.2110586 2110586 · DOI
  62. May J. M. (1988). Inhibition of hexose transport by adenosine derivatives in human erythrocytes. J. Cell. Physiol. 135, 332– 338. 10.1002/jcp.1041350222 3372599 · DOI
  63. Merlini M. Meyer E. P. Ulmann-Schuler A. Nitsch R. M. (2011). Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol. 122, 293– 311. 10.1007/s00401-011-0834-y 21688176 PMC3168476 · DOI · Paper page
  64. Mooradian A. D. Chung H. C. Shah G. N. (1997). GLUT-1 expression in the cerebra of patients with Alzheimer's disease. Neurobiol. Aging 18, 469– 474. 10.1016/S0197-4580(97)00111-5 9390772 · DOI · Paper page
  65. Mosconi L. Andrews R. D. Matthews D. C. (2013). Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia. J. Alzheimer's Dis. 35, 509– 524. 10.3233/JAD-121867 23478305 · DOI
  66. Mosconi L. Brys M. Glodzik-Sobanska L. De Santi S. Rusinek H. de Leon M. J. (2007a). Early detection of Alzheimer's disease using neuroimaging. Exp. Gerontol. 42, 129– 138. 10.1016/j.exger.2006.05.016 16839732 · DOI
  67. Mosconi L. De Santi S. Li J. Tsui W. H. Li Y. Boppana M.. (2008). Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol. Aging 29, 676– 692. 10.1016/j.neurobiolaging.2006.12.008 17222480 PMC2430185 · DOI · Paper page
  68. Mosconi L. Mistur R. Switalski R. Tsui W. H. Glodzik L. Li Y.. (2009). FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 36, 811– 822. 10.1007/s00259-008-1039-z 19142633 PMC2774795 · DOI · Paper page
  69. Mosconi L. Sorbi S. De Leon M. J. Li Y. Nacmias B. Myoung P. S.. (2006). Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J. Nucl. Med. 47, 1778– 1786. 17079810
  70. Mosconi L. Tsui W. H. Rusinek H. De Santi S. Li Y. Wang G. J.. (2007b). Quantitation, regional vulnerability, and kinetic modeling of brain glucose metabolism in mild Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 34, 1467– 1479. 10.1007/s00259-007-0406-5 17406865 · DOI
  71. Muhič M. Vardjan N. Chowdhury H. H. Zorec R. Kreft M. (2015). Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes. J. Biol. Chem. 290, 11167– 11176. 10.1074/jbc.M114.629063 25792745 PMC4409273 · DOI
  72. Mullins R. J. Diehl T. C. Chia C. W. Kapogiannis D. (2017). Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer's disease. Front. Aging Neurosci. 9: 118. 10.3389/fnagi.2017.00118 28515688 PMC5413582 · DOI
  73. Niccoli T. Cabecinha M. Tillmann A. Kerr F. Wong C. T. Cardenes D.. (2016). Increased glucose transport into neurons rescues Aβ toxicity in drosophila. Curr. Biol. 26, 2291– 2300. 10.1016/j.cub.2016.07.017 27524482 PMC5026704 · DOI
  74. Nicholson R. M. Kusne Y. Nowak L. A. LaFerla F. M. Reiman E. M. Valla J. (2010). Regional cerebral glucose uptake in the 3xTG model of Alzheimer's disease highlights common regional vulnerability across AD mouse models. Brain Res. 1347, 179– 185. 10.1016/j.brainres.2010.05.084 20677372 PMC2974951 · DOI · Paper page
  75. Ou Y. N. Xu W. Li J. Q. Guo Y. Cui M. Chen K. L.. (2019). FDG-PET as an independent biomarker for Alzheimer's biological diagnosis: a longitudinal study. Alzheimer's Res. Ther. 11, 1– 11. 10.1186/s13195-019-0512-1 31253185 PMC6599313 · DOI · Paper page
  76. Pardridge W. M. (1994). Glucose transport and phosphorylation: which is rate limiting for brain glucose utilization? Ann. Neurol. 35, 511– 512. 10.1002/ana.410350503 8179296 · DOI
  77. Pardridge W. M. (2009). Alzheimer's disease drug development and the problem of the blood-brain barrier. Alzheimers. Dement. 5, 427– 432. 10.1016/j.jalz.2009.06.003 19751922 PMC2756824 · DOI
  78. Patching S. G. (2017). Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery. Mol. Neurobiol. 54, 1046– 1077. 10.1007/s12035-015-9672-6 26801191 · DOI
  79. Piert M. Koeppe R. A. Giordani B. Berent S. Kuhl D. E. (1996). Diminished glucose transport and phosphorylation in Alzheimer's disease determined by dynamic FDG-PET. J. Nucl. Med. 37, 201– 208. 8667045
  80. Piroli G. G. Grillo C. A. Hoskin E. K. Znamensky V. Katz E. B. Milner T. A.. (2002). Peripheral glucose administration stimulates the translocation of GLUT8 glucose transporter to the endoplasmic reticulum in the rat hippocampus. J. Comp. Neurol. 452, 103– 114. 10.1002/cne.10368 12271485 · DOI
  81. Pujol-Gimenez J. Martisova E. Perez-Mediavilla A. Lostao M. P. Ramirez M. J. (2014). Expression of the glucose transporter GLUT12 in Alzheimer's disease patients. J. Alzheimer's Dis. 42, 97– 101. 10.3233/JAD-132498 24820014 · DOI
  82. Purcell S. H. Aerni-Flessner L. B. Willcockson A. R. Diggs-Andrews K. A. Fisher S. J. Moley K. H. (2011). Improved insulin sensitivity by GLUT12 overexpression in mice. Diabetes 60, 1478– 1482. 10.2337/db11-0033 21441439 PMC3292321 · DOI
  83. Reagan L. P. (2002). Glucose, stress, and hippocampal neuronal vulnerability. Int. Rev. Neurobiol. 51, 289– 324. 10.1016/S0074-7742(02)51009-6 12420363 · DOI
  84. Reitz C. Brayne C. Mayeux R. (2011). Epidemiology of Alzheimer disease. Nat. Rev. Neurol. 7, 137– 152. 10.1038/nrneurol.2011.2 21304480 PMC3339565 · DOI · Paper page
  85. Sajja R. K. Prasad S. Cucullo L. (2014). Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line. Fluids Barriers CNS 11, 1– 14. 10.1186/2045-8118-11-8 24708805 PMC3985548 · DOI
  86. Salkovic-Petrisic M. Osmanovic-Barilar J. Knezovic A. Hoyer S. Mosetter K. Reutter W. (2014). Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. Neuropharmacology 77, 68– 80. 10.1016/j.neuropharm.2013.09.002 24055495 · DOI
  87. Scheltens P. Blennow K. Breteler M. M. B. de Strooper B. Frisoni G. B. Salloway S.. (2016). Alzheimer's disease. Lancet 388, 505– 517. 10.1016/S0140-6736(15)01124-1 26921134 · DOI · Paper page
  88. Shang J. Yamashita T. Tian F. Li X. Liu X. Shi X.. (2019). Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer's disease model mouse. Brain Res. 1723: 146379. 10.1016/j.brainres.2019.146379 31415766 · DOI
  89. Simpson I. A. Appel N. M. Hokari M. Oki J. Holman G. D. Maher F.. (1999). Blood – brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited. J. Neurochem. 72, 238– 247. 10.1046/j.1471-4159.1999.0720238.x 9886075 · DOI · Paper page
  90. Simpson I. A. Chundu K. R. Davies-Hill T. Honer W. G. Davies P. (1994). Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann. Neurol. 35, 546– 551. 10.1002/ana.410350507 8179300 · DOI · Paper page
  91. Simpson I. A. Dwyer D. Malide D. Moley K. H. Travis A. Vannucci S. J. (2008). The facilitative glucose transporter GLUT3:20 Years of distinction. Am. J. Physiol. - Endocrinol. Metab. 295, 242– 253. 10.1152/ajpendo.90388.2008 18577699 PMC2519757 · DOI · Paper page
  92. Small G. W. Ercoli L. M. Silverman D. H. S. Huang S.-C. Komo S. Bookheimer S. Y.. (2000). Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 97, 6037– 6042. 10.1073/pnas.090106797 10811879 PMC18554 · DOI · Paper page
  93. Stuart C. A. Howell M. E. A. Zhang Y. Yin D. (2009). Insulin-stimulated translocation of glucose transporter (GLUT) 12 parallels that of GLUT4 in normal muscle. J. Clin. Endocrinol. Metab. 94, 3535– 3542. 10.1210/jc.2009-0162 19549745 PMC2741719 · DOI
  94. Szablewski L. (2017). Glucose transporters in brain: in health and in Alzheimer's disease. J. Alzheimer's Dis. 55, 1307– 1320. 10.3233/JAD-160841 27858715 · DOI · Paper page
  95. Takakura Y. Kuentzel S. L. Raub T. J. Davies A. Baldwin S. A. Borchardt R. T. (1991). Hexose uptake in primary cultures of bovine brain microvessel endothetial cells. I. Basic characteristics and effects of d-glucose and insulin. BBA - Biomembr. 1070, 1– 10. 10.1016/0005-2736(91)90139-Y 1751515 · DOI
  96. Terry R. D. Masliah E. Salmon D. P. Butters N. DeTeresa R. Hill R.. (1991). Physical basis of cognitive alterations in alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572– 580. 10.1002/ana.410300410 1789684 · DOI · Paper page
  97. Van Der Velpen V. Teav T. Gallart-Ayala H. Mehl F. Konz I. Clark C.. (2019). Systemic and central nervous system metabolic alterations in Alzheimer's disease. Alzheimer's Res. Ther. 11: 93. 10.1186/s13195-019-0551-7 31779690 PMC6883620 · DOI
  98. Vannucci S. J. Koehler-stec E. M. Li K. Reynolds T. H. Clark R. Simpson I. A. (1998). GLUT4 glucose transporter expression in rodent brain: effect of diabetes. 797, 1– 11. 10.1016/S0006-8993(98)00103-6 9630471 · DOI
  99. Wang W. Yu J.-T. Zhang W. Cui W.-Z. Wu Z.-C. Zhang Q.. (2012). Genetic association of SLC2A14 polymorphism With Alzheimer's disease in a han chinese population. J. Mol. Neurosci. 47, 481– 484. 10.1007/s12031-012-9748-y 22421804 · DOI
  100. Watson G. S. Peskind E. R. Asthana S. Purganan K. Wait C. Chapman D.. (2003). Insulin increases CSF Abeta42 levels in normal older adults. Neurology 60, 1899– 1903. 10.1212/01.WNL.0000065916.25128.25 12821730 · DOI
  101. Yamamoto N. Matsubara T. Sobue K. Tanida M. Kasahara R. Naruse K.. (2012). Brain insulin resistance accelerates Aβ fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes. J. Neurochem. 121, 619– 628. 10.1111/j.1471-4159.2012.07668.x 22260232 · DOI
  102. Yoon S. O. Park D. J. Ryu J. C. Ozer H. G. Tep C. Shin Y. J.. (2012). JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron 75, 824– 837. 10.1016/j.neuron.2012.06.024 22958823 PMC3438522 · DOI
  103. Yun S. P. Kam T. Panicker N. Kim S. Oh Y. Park J.. (2018). Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson ' s disease. Nat. Med. 24, 931– 938. 10.1038/s41591-018-0051-5 29892066 PMC6039259 · DOI · Paper page
  104. Zeller K. Rahner-Welsch S. Kuschinsky W. (1997). Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. J. Cereb. Blood Flow Metab. 17, 204– 209. 10.1097/00004647-199702000-00010 9040500 · DOI

Cited by

Sorted by citations

Authors
Kyrtata, N., Emsley, H. C. A., Sparasci, O., Parkes, L. M., & Dickie, B. R.
Affiliations
  • University Hospitals of Morecambe Bay NHS Foundation Trust (GB)
  • Lancashire Teaching Hospitals NHS Foundation Trust (GB)
  • Greater Manchester Mental Health NHS Foundation Trust (GB)
  • Manchester Academic Health Science Centre (GB)
Corresponding author
Dickie, Ben R.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2021-05-20
Volume
15
Pages
626636-626636
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2021.626636
PMC
PMC8173065
OpenAlex
W3161579083
Cited by
171
References
12
Citations by year
2026: 31 · 2025: 50 · 2024: 37 · 2023: 28 · 2022: 22 · 2021: 3
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lancaster EPrints (Lancaster University) (submittedVersion)
Funders
Medical Research Council
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
Alzheimer's disease, glucose transport, glucose transporters, GLUT1, GLUT3, GLUT2, GLUT12, cerebral glucose hypometabolism, amyloid-beta, blood-brain barrier, hippocampus, antidiabetic drugs, drug repurposing, brain glucose metabolism

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review