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

doi:10.1038/nn.3966

. 2015 Apr;18(4):521-530.

doi: 10.1038/nn.3966. Epub 2015 Mar 2.

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

Ethan A Winkler^#^{1

2}, Yoichiro Nishida^#^{3

4}, Abhay P Sagare^#¹, Sanket V Rege¹, Robert D Bell³, David Perlmutter³, Jesse D Sengillo^{1

3}, Sara Hillman³, Pan Kong¹, Amy R Nelson¹, John S Sullivan¹, Zhen Zhao¹, Herbert J Meiselman⁵, Rosalinda B Wendy⁵, Jamie Soto⁶, E Dale Abel⁶, Jacob Makshanoff¹, Edward Zuniga¹, Darryl C De Vivo⁷, Berislav V Zlokovic^{1

5}

Affiliations

¹ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
² Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.
³ Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
⁴ Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
⁵ Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
⁶ Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁷ Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University New York, NY, USA.

^# Contributed equally.

PMID: 25730668
PMCID: PMC4734893
DOI: 10.1038/nn.3966

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

Ethan A Winkler et al. Nat Neurosci. 2015 Apr.

. 2015 Apr;18(4):521-530.

doi: 10.1038/nn.3966. Epub 2015 Mar 2.

Authors

Affiliations

¹ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
² Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.
³ Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester School of Medicine & Dentistry, Rochester, NY.
⁴ Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
⁵ Departrment of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
⁶ Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁷ Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University New York, NY, USA.

^# Contributed equally.

PMID: 25730668
PMCID: PMC4734893
DOI: 10.1038/nn.3966

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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Figures

**Figure 1. Microvascular and cerebral blood flow reductions and diminished glucose uptake in GLUT1-deficient *APP^Sw/0* mice**
(**a-b**) Quantification of lectin-positive microvascular profiles in cortex (b) and hippocampus (b) in 2-week, 1- and 6-month old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-6 mice per group; *p<0.05. (**c-d**) Representative *in vivo* multiphoton fluorescent angiograms obtained following intravascular injection of fluorescein-conjugated dextran (MW: 70 kDa) **(c)** and quantification of perfused microvascular length (d) in 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 50 μm. Mean ± SEM, n=3-4 mice per group; *p<0.05 or **p<0.01 (**e-f**) Representative C¹⁴-iodoantipyrine (C¹⁴-IAP) autoradiography (e) and quantification of C¹⁴-IAP autoradiograms measuring regional blood flow in the somatosensory cortex and CA1 hippocampal subfield (f) in 1- and 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 1 mm. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. (g) Cerebral blood flow (CBF) responses to brain activation in the somatosensory cortex of 1-month, 6-month and 16-month old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. (h) Quantification of C¹⁴-2-deoxyglucose (2-DG) autoradiograms measuring regional glucose uptake in the somatosensory cortex and CA1 hippocampal subfield in 2-3 week-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=5-7 mice per group in a, b, d, f and g; and n=3 mice per group in h; *p<0.05 or **p<0.01.

**Figure 2. GLUT1 deficiency leads to early BBB breakdown in *Slc2a1^+/−* and *Slc2a1^+/−APP^Sw/0* mice**
(a) Representative confocal microscopy analysis of fibrin (red) and lectin-positive capillaries (white) in 2-week-old *Slc2a1^+/+*,*Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 25 μm. (**b-c**) Quantification of extravascular fibrin (b) and immunoglobulin G (IgG) (c) deposits in 2-week old *Slc2a1^+/+*, *Slc2a1^+/−, Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. (**d-f**) Representative immunoblotting of fibrin and IgG levels in capillary-depleted brain tissue (d) and quantification of IgG (e) and fibrin (f) relative abundance in capillary-depleted brains in 2-week-old *Slc2a1^+/+*, *Slc2a1^+/−, Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. β-actin was used as a loading control. Mean ± SEM, n=3-5 mice per group; **p<0.01. (**g-i**) The tight junction proteins occludin or zonula occludens-1 (ZO-1) (green) and lectin-positive capillary profiles (red) (g) and quantification of endothelial occludin (h) and ZO-1 (i) length in the microvessels in 2-week-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mouse hippocampus. Scale bar, 25 μm. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. (**j-k**) Negative correlation between the extracellular fibrin (j) or IgG deposits (k) and decreased occludin length in the microvessels in 2-week-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mouse hippocampus. (l) Representative immunoblotting analysis of microvascular ZO-1, occludin and claudin-5 (l) and their respective protein abundance in microvessels (m) in a 2-week-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mouse. β-actin was used as loading control. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. Full length blots are presented in Supplementary Figure 11.

**Figure 3. Aβ pathology in GLUT1-deficient *APP^Sw/0* mice and reversal by LRP1 and GLUT1 re-expression**
(**a-b**) Cortical and hippocampal Aβ₄₀ (a) and Aβ₄₂ (b) levels in 1-, 6- and 16-month old *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-6 mice per group; *p<0.05 or **p<0.01. (**c-d**) Aβ-immunodetection (green) in the somatosensory cortex and CA1 hippocampal subfield (c) and Aβ load (d) in 16-month old *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 200 μm. Mean ± SEM, n=4-5 mice per group; *p<0.01. (e) Immunoblotting for the low-density lipoprotein receptor-related protein 1 (LRP1) in isolated microvessels (upper panel) and quantification (lower panel) in 16-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=4 mice per group; *p<0.05 or **p<0.01. (f) Clearance of [¹²⁵I]-labeled human synthetic Aβ₄₀ from CA1 hippocampal subfield in 16-month-old *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. [¹⁴C]inulin was used to assess brain interstitial fluid (ISF) bulk flow. Time, 30 minutes post-injection. Mean ± SEM, n=3-5 mice per group; *p<0.05. (g) [¹²⁵I]-Aβ₄₀ clearance via BBB and ISF bulk flow (from the data shown in f). (**h-i**) Aβ-immunodetection (green) in CA1 hippocampal subfield (h) and quantification of Aβ-positive area (i) in 10-month-old *Slc2a1^+/−APP^Sw/0* mouse injected with empty adenovirus (Ad.Ctrl) and adenovirus carrying *LRP1* minigene (Ad.mLRP1). Black, Ad.Ctrl hippocampus; White, Ad.mLRP1 hippocampus. Scale bar, 300 μm. Mean ± SEM, n=3 mice; **p<0.01. (j) CA1 hippocampal guanidine soluble Aβ₄₀ (black) and Aβ₄₂ (grey) levels in 10-month old *Slc2a1^+/−APP^Sw/0* mice injected with Ad.Ctrl and Ad.mLRP1. Graph - percent change of Ad.mLRP1 hippocampus to Ad.Ctrl hippocampus. Mean ± SEM, n=3 mice per group; *p<0.05. (**k-m**) Aβ-immunodetection (green) in CA1 hippocampal subfield (k) and quantification of Aβ-positive area (l) in 8-10-month-old *Slc2a1^+/−APP^Sw/0* mouse injected with empty adenovirus (Ad.Ctrl) and adenovirus carrying *Slc2a1* gene (Ad.Slc2a1). Black, Ad.Ctrl hippocampus; White, Ad.Slc2a1 hippocampus. Scale bar, 300 μm. Mean ± SEM, n=3 mice; *p<0.05. (m) CA1 hippocampal guanidine soluble Aβ₄₀ (black) and Aβ₄₂ (grey) levels in 8-10-month-old *Slc2a1^+/−APP^Sw/0* mice injected with Ad.Ctrl and Ad.Slc2a1. Graph - percent change of Ad.Slc2a1 hippocampus to Ad.Ctrl hippocampus. Mean ± SEM, n=3 mice; *p<0.05. Full length blots are presented in Supplementary Figure 11.

**Figure 4. Neuronal dysfunction in GLUT1-deficient *APP^Sw/0* mice**
(a) Representative time-lapse-imaging analysis of voltage sensitive dye (VSD) signal response to hind-limb somatosensory cortex stimulation in 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 500 μm. (**b-d**) Quantitative time-lapse-imaging profile analysis of VSD response to hind-limb somatosensory cortex stimulation in 2-week-old (b), 1-month-old (c) and 6-month-old (d) *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. ΔF/F₀ indicates the percentage change in fluorescence from the baseline fluorescent signal following stimulation. (**e-f**) Quantification of peak fluorescent VSD signal amplitude (e) and time-to-peak latency (f) in 2-week-old, 1-month-old and 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-4 mice per group; *p<0.05 or **p<0.01.

**Figure 5. Accelerated cognitive impairment in GLUT1-deficient *APP^Sw/0* mice**
(**a-c**) Quantification of exploratory preference measuring hippocampal-dependent novel object location memory (a), novel object recognition memory (b), nest construction score (c) and mean locomotor activity (d) in 1- and 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=9-15 mice per group; *p<0.05 or **p<0.01. (e) Representative high-magnification bright-field microscopy microscopy analysis of Golgi-Cox staining showing dendritic spine density in the CA1 hippocampal region of 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. (f) Quantification of dendritic spine density in 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01.

**Figure 6. Accelerated neurodegenerative changes in GLUT1-deficient *APP^Sw/0* mice**
(a) SMI-311 immunodetection showing neurites (green) in the CA1 hippocampal region of 16-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 50 μm. (b) Quantification of SMI-311-positive neuritic density in somatosensory cortex and CA1 hippocampal subfield in 1-, 6- and 16-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 50 μm. Mean ± SEM, n=3-4 mice per group; *p<0.05 or **p<0.01. (c) NeuN-positive neurons (green) in the CA1 hippocampal subfield of 16-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. (d) Quantification of the number of NeuN-positive neurons in somatosensory cortex and CA1 hippocampal subfield in 1-, 6- and 16-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Mean ± SEM, n=3-6 mice per group; *p<0.05 or **p<0.01. (**e-f**) Representative low-magnification bright-field microscopy of mouse brains (e) and quantification of maximal brain diameter (f) in 6-month-old *Slc2a1^+/+*, *Slc2a1^+/−*, *Slc2a1^+/+APP^Sw/0* and *Slc2a1^+/−APP^Sw/0* mice. Scale bar, 5 mm. Mean ± SEM, n=5-6 mice per group; *p<0.05 or **p<0.01.

**Figure 7. GLUT1 deficiency in endothelial cells (*Slc2a1^lox/+Tie2-Cre^+/0* mice), but not astrocytes (*Slc2a1^lox/+GFAP-Cre^+/0* mice) leads to early BBB breakdown**
(a) Representative confocal microscopy analysis of plasma-derived fibrin (red) and CD31-positive capillaries (white) in 2-week-old *Slc2a1^lox/+*, *Slc2a1^lox/+Tie2-Cre^+/0*, *Slc2a1^lox/+GFAP-Cre^+/0* mice. Scale bar, 25 μm. (**b-c**) Quantification of extravascular fibrin (b) and IgG (c) positive deposits in 2-week old *Slc2a1^lox/+*, *Slc2a1^lox/+Tie2-Cre^+/0*, *Slc2a1^lox/+GFAP-Cre^+/0* mice. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. (d) Representative confocal microscopy analysis of the tight junction proteins occludin or zonula occludens-1 (ZO-1) (green) and CD31-positive capillary profiles. (**e-f**) Quantification of endothelial occludin (e) and ZO-1 (f) tight junctional length in the microvessels in 2-week-old *Slc2a1^lox/+*, *Slc2a1^lox/+Tie2-Cre^+/0*, *Slc2a1^lox/+GFAP-Cre^+/0* mice. Scale bar, 25 μm. Mean ± SEM, n=3-5 mice per group; *p<0.05 or **p<0.01. (**g-h**) Negative correlation between extracellular fibrin (g) or IgG deposits (h) and decreased occludin length in the microvessels in 2-week-old *Slc2a1^lox/+*, *Slc2a1^lox/+Tie2-Cre^+/0*, *Slc2a1^lox/+GFAP-Cre^+/0* mice.

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Sugar and Alzheimer's disease: a bittersweet truth.
Iadecola C. Iadecola C. Nat Neurosci. 2015 Apr;18(4):477-8. doi: 10.1038/nn.3986. Nat Neurosci. 2015. PMID: 25811474 Free PMC article.

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References

1. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. - PubMed
1. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 2011;12:723–738. - PMC - PubMed
1. Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2007;27:1766–1791. - PMC - PubMed
1. Deng D, et al. Crystal structure of the human glucose transporter GLUT1. Nature. 2014;510:121–125. - PubMed
1. Allen A, Messier C. Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice. Behav. Brain Res. 2013;240:95–102. - PubMed

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[1] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. - PubMed

[2] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. - PubMed

[3] Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 2011;12:723–738. - PMC - PubMed

[4] Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 2011;12:723–738. - PMC - PubMed

[5] Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2007;27:1766–1791. - PMC - PubMed

[6] Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2007;27:1766–1791. - PMC - PubMed

[7] Deng D, et al. Crystal structure of the human glucose transporter GLUT1. Nature. 2014;510:121–125. - PubMed

[8] Deng D, et al. Crystal structure of the human glucose transporter GLUT1. Nature. 2014;510:121–125. - PubMed

[9] Allen A, Messier C. Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice. Behav. Brain Res. 2013;240:95–102. - PubMed

[10] Allen A, Messier C. Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice. Behav. Brain Res. 2013;240:95–102. - PubMed

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

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

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