Journal article
GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration
Nature neuroscience, Vol.18(4), pp.521-530
04/2015
DOI: 10.1038/nn.3966
PMCID: PMC4734893
PMID: 25730668
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.
Details
- Title: Subtitle
- GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration
- Creators
- Ethan A Winkler - Department of Neurological Surgery, University of California San Francisco, San Francisco, CAYoichiro Nishida - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, JapanAbhay P Sagare - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CASanket V Rege - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CARobert D Bell - Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NYDavid Perlmutter - Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NYJesse D Sengillo - Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NYSara Hillman - Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NYPan Kong - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CAAmy R Nelson - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CAJohn S Sullivan - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CAZhen Zhao - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CAHerbert J Meiselman - Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CARosalinda B Wendy - Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CAJamie Soto - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USAE Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USAJacob Makshanoff - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CAEdward Zuniga - Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CADarryl C De Vivo - Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University New York, NY, USABerislav V Zlokovic - Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.18(4), pp.521-530
- DOI
- 10.1038/nn.3966
- PMID
- 25730668
- PMCID
- PMC4734893
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Publisher
- United States
- Grant note
- AG039452 / NIA NIH HHS R01 AG039452 / NIA NIH HHS R01 DK092065 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS R01 AG023084 / NIA NIH HHS AG023084 / NIA NIH HHS NS034467 / NINDS NIH HHS R01 NS034467 / NINDS NIH HHS R01DK092065 / NIDDK NIH HHS
- Language
- English
- Date published
- 04/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024402602771
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