Cited by 689Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.

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

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Abstract

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid β-peptide (Aβ) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

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Metadata

Authors
Winkler, E. A., Nishida, Y., Sagare, A. P., Rege, S. V., Bell, R. D., Perlmutter, D., Sengillo, J. D., Hillman, S., Kong, P., Nelson, A. R., Sullivan, J. S., Zhao, Z., Meiselman, H. J., Wenby, R. B., Soto, J., Abel, E. D., Makshanoff, J., Zuniga, E., De Vivo, D. C., & Zlokovic, B. V.
Affiliations
  • University of Southern California (US)
  • Tokyo Medical and Dental University (JP)
  • University of Rochester Medicine (US)
  • University of Iowa (US)
Venue
Nature Neuroscience
Published
2015-03-02
Volume
18
Issue
4
Pages
521-530
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W1974266381
Cited by
689
References
63
Citations by year
2026: 65 · 2025: 72 · 2024: 65 · 2023: 62 · 2022: 79 · 2021: 78 · 2020: 62 · 2019: 49 · 2018: 52 · 2017: 47 · 2016: 38 · 2015: 20
FWCI
27.97
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Southern California
  • National Institutes of Health
  • National Institute on Aging (R01AG023084, R01AG039452, R37AG023084, AG039452, RF1AG039452, AG023084)
  • National Heart, Lung, and Blood Institute (U01HL087947)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092065)
  • National Institute of Neurological Disorders and Stroke (NS034467, R37NS034467, R01NS034467)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
GLUT1, Alzheimer's disease, blood-brain barrier, brain endothelium, amyloid-beta, amyloid-beta clearance, glucose transport, neurodegeneration, cerebrovascular dysfunction, cognitive impairment, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Cerebrovascular Circulation, Disease Models, Animal, Endothelium, Vascular, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, Glucose Transporter Type 1, Mice

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