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GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration
Open accessAbstract
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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“The Slc2a1 + / -mice with haploid deficiency in glucose transporter GLUT1 in brain endothelial cells develop microvascular reductions with BBB breakdown including loss of TJ and basement membrane proteins (649), whereas knockout of murine Mfsd2a gene results in not only diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine, but also leads to dysregulated cave”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Since glucose concentration is lower in the brain interstitial fluid (ISF) compared with plasma, GLUT1 favors blood-to-brain transport of circulating glucose (141, 390, 649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Glut1 + / -mice phenocopy human pathology, and develop initially within 2-3 wk of age BBB breakdown with loss of tight junctions and diminished glucose uptake by the brain, which is followed by microvascular regression, reduced brain perfusion and development of secondary neurodegenerative changes, microcephaly, and loss of cortical and hippocampal neurons (649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Experimental studies also support diminished transport of 14 C-labeled glucose across the BBB in haploinsufficient Slc2a1 + / -mice lacking ~50% copies of the GLUT1 BBB transporter (649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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“Reduced activity and expression of the GLUT-1 transporter in the BBB suggest decreased glucose uptake and utilization by the brain,360,363 which may further exacerbate cerebrovascular degeneration, BBB breakdown, and Aβ pathology in models overexpressing APP, inducing neurodegeneration and cognitive deficits (Fig. 4).364”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [364]
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“reduced GLUT1 levels may also inhibit LRP1 transcriptionally via sterol regulatory element binding protein 2 (SREBP2) (649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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“Brain endothelial specific or enriched transporters are often indispensable for BBB barriergenesis, as for example, the glucose transporter-1 (GLUT1) (649), sodium-dependent lysophosphatidylcholine (LPC) symporter, the major facilitator superfamily (MFS) domain-containing protein 2a (MFSD2A) (62), and monocarboxylic acid transporter MCT8 (611).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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“Since glucose concentration is lower in the brain interstitial fluid (ISF) compared with plasma, GLUT1 favors blood-to-brain transport of circulating glucose (141, 390, 649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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In the citing paper
“GLUT1 is expressed in endothelial cells, but not in neurons (141, 649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
The cited source says what the claim attributes to it.
In the citing paper
“For example, LRP1 minigene delivery to the BBB by viral vectors facilitates A 𝛃 clearance and attenuates A 𝛃 pathology (649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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In the citing paper
“which we know leads to severe neurological phenotype in the GLUT1-deficiency syndrome (630, 649).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [649]
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Cites
1 retracted
RETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Sagare, A. P., Bell, R. D., Zhao, Z., Ma, Q., Winkler, E. A., Ramanathan, A., & Zlokovic, B. V. (2013) · Nature Communications · doi:10.1038/ncomms3932 · Cited by 589
Self-citationRetractedCorrelative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969
Bell, R. D., Winkler, E. A., Sagare, A. P., Singh, I., LaRue, B., Deane, R., & Zlokovic, B. V. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.043 · Cited by 1,448
Self-citationRAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., et al. (2003) · Nature Medicine · doi:10.1038/nm890 · Cited by 1,426
Shibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10498 · Cited by 1,413
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293
Self-citationAssessing nest building in mice
Deacon, R. M. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.170 · Cited by 1,115
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave-Gassiot, A., Zhang, X., Wenk, M. R., Goh, E. L. K., & Silver, D. L. (2014) · Nature · doi:10.1038/nature13241 · Cited by 1,048
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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Leng, F., & Edison, P. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-020-00435-y · Cited by 3,179
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076
Self-citationBlood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,312
Self-citationThe Cellular Phase of Alzheimer’s Disease
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Establishment and Dysfunction of the Blood-Brain Barrier
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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)
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-03-02
- Volume
- 18
- Issue
- 4
- Pages
- 521-530
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4734893
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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