GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration.
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.
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.
Ethan A
EA
Winkler
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.|Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Yoichiro
Y
Nishida
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Abhay P
AP
Sagare
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Sanket V
SV
Rege
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
Robert D
RD
Bell
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
David
D
Perlmutter
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
Jesse D
JD
Sengillo
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
Sara
S
Hillman
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Pan
P
Kong
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Amy R
AR
Nelson
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
John S
JS
Sullivan
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Zhen
Z
Zhao
Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Herbert J
HJ
Meiselman
Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Rosalinda B
RB
Wendy
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Jamie
J
Soto
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
E Dale
ED
Abel
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Jacob
J
Makshanoff
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Edward
E
Zuniga
Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University New York, NY, USA.
Darryl C
DC
De Vivo
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Berislav V
BV
Zlokovic
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051272:Glucose Transporter Type 1 / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D051272:Glucose Transporter Type 1