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Cited by 9Cerebrovascular and genetic disordersNeurological Disease Mechanisms and TreatmentsBarrier Structure and Function Studies

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

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Panahi, Mahmod, Rodriguez, Patricia Rodriguez, Fereshtehnejad, Seyed-Mohammad, Arafa, Donia, Bogdanovic, Nenad, Winblad, Bengt, Cedazo-Minguez, Angel, Rinne, Juha +5 more·2020·Frontiers in Genetics
DOI 10.3389/fgene.2020.01022PMC PMC7522350
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Abstract

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that glucose metabolism is disrupted in VSMCs in CADASIL, we investigated postmortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake ability in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in glucose transporters in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. The impaired ability of glucose uptake is rescue by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis.

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  • Neuronal glucose utilization is largely insulin-independent, relying on facilitative glucose transporters, particularly GLUT1 in endothelial cells and astrocytes and GLUT3 in neurons.

    “While peripheral tissues depend heavily on insulin for glucose uptake, neuronal glucose utilization is largely insulin-independent, relying instead on facilitative glucose transporters (GLUTs), particularly GLUT1 in endothelial cells and astrocytes and GLUT3 in neurons [71].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [71]

    The Introduction says glucose transport is mainly facilitated by GLUTs, and the Discussion identifies GLUT1 as the major transporter in endothelial cells. The paper’s insulin-independence findings concern vascular smooth muscle cells, not neurons; the passages do not establish that neuronal glucose use is largely insulin-independent or identify GLUT1 in astrocytes and GLUT3 in neurons (pages not supplied). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Aβ oligomers can directly interact with glucose transporters, promoting their internalization and reducing surface availability, thereby limiting glucose entry into neurons.

    “Experimental studies indicate that Aβ oligomers can directly interact with glucose transporters, promoting their internalization and reducing surface availability, thereby limiting glucose entry into neurons [70, 71].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [71]

    The Discussion reports reduced glucose-transporter expression in CADASIL vascular smooth muscle cells and brain microvessels, not in neurons. Searches for Aβ oligomers, direct transporter interaction, and internalization found no passage addressing the claimed mechanism in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Panahi, M., Rodriguez, P. R., Fereshtehnejad, S.-M., Arafa, D., Bogdanovic, N., Winblad, B., Cedazo-Minguez, A., Rinne, J., Darreh-Shori, T., Hase, Y., Kalaria, R. N., Viitanen, M., & Behbahani, H.
Affiliations
  • Karolinska Institutet (SE)
  • University of Turku (FI)
  • Newcastle University (GB)
Corresponding author
  • Kalaria, Raj N.
  • Behbahani, Homira
ORCID
Venue
Frontiers in Genetics
Publisher
Frontiers Media SA
Published
2020-09-15
Volume
11
Pages
1022-1022
ISSN
1664-8021 (ISSN-L)
DOI
10.3389/fgene.2020.01022
PMC
PMC7522350
OpenAlex
W3092274335
Cited by
9
References
5
Citations by year
2025: 4 · 2024: 2 · 2023: 2 · 2022: 1
FWCI
0.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UTUPub (University of Turku) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Gun och Bertil Stohnes Stiftelse
  • Stiftelsen Olle Engkvist Byggmästare
  • Stiftelsen för Gamla Tjänarinnor
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
CADASIL, NOTCH3 mutations, vascular smooth muscle cells, glucose transporters, GLUT4, GLUT2, glucose uptake, insulin, cerebral arteriopathy, cerebral small vessel disease, subcortical ischemic stroke, glucose metabolism

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