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Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology

View ORCID ProfileShannon L. Macauley, Molly S. Stanley, Emily E. Caesar, William R. Moritz, Annie R. Bice, Nildris Cruz-Diaz, Caitlin M. Carroll, Stephen M. Day, John Grizzanti, Thomas E. Mahan, James A. Snipes, Timothy E. Orr, Joseph P. Culver, Maria S. Remedi, Colin G. Nichols, View ORCID ProfileCeleste M. Karch, Laura A. Cox, Debra I. Diz, Adam Q. Bauer, David M. Holtzman
doi: https://doi.org/10.1101/2021.08.11.455969
Shannon L. Macauley
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
2Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 2710
4Alzheimer’s Disease Research Center, Wake Forest School of Medicine, Winston Salem, NC 2710
5Center for Diabetes and Metabolism, Wake Forest School of Medicine, Winston Salem, NC 2710
6Center for Precision Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
8Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC 2710
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
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  • ORCID record for Shannon L. Macauley
  • For correspondence: smacaule@wakehealth.edu
Molly S. Stanley
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
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Emily E. Caesar
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
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William R. Moritz
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
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Annie R. Bice
10Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110
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Nildris Cruz-Diaz
3Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC 2710
7Hypertension & Vascular Research Center, Wake Forest School of Medicine, Winston Salem, NC 2710
8Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC 2710
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Caitlin M. Carroll
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
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Stephen M. Day
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
2Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 2710
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John Grizzanti
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
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Thomas E. Mahan
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
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James A. Snipes
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
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Timothy E. Orr
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
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Joseph P. Culver
10Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110
12The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
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Maria S. Remedi
14Center for Excitability and Membrane Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
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Colin G. Nichols
14Center for Excitability and Membrane Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
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Celeste M. Karch
11Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110
12The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
13Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
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Laura A. Cox
1Department of Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC 2710
5Center for Diabetes and Metabolism, Wake Forest School of Medicine, Winston Salem, NC 2710
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Debra I. Diz
3Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC 2710
7Hypertension & Vascular Research Center, Wake Forest School of Medicine, Winston Salem, NC 2710
8Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC 2710
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Adam Q. Bauer
12The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
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David M. Holtzman
9Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
12The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
13Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT

Hyperexcitability is a defining feature of Alzheimer’s disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (Aβ), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD.

Graphical abstract Targeting vascular KATP channel activity for the treatment of Alzheimer’s disease pathology.

Figure

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 12, 2021.
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Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology
Shannon L. Macauley, Molly S. Stanley, Emily E. Caesar, William R. Moritz, Annie R. Bice, Nildris Cruz-Diaz, Caitlin M. Carroll, Stephen M. Day, John Grizzanti, Thomas E. Mahan, James A. Snipes, Timothy E. Orr, Joseph P. Culver, Maria S. Remedi, Colin G. Nichols, Celeste M. Karch, Laura A. Cox, Debra I. Diz, Adam Q. Bauer, David M. Holtzman
bioRxiv 2021.08.11.455969; doi: https://doi.org/10.1101/2021.08.11.455969
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Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology
Shannon L. Macauley, Molly S. Stanley, Emily E. Caesar, William R. Moritz, Annie R. Bice, Nildris Cruz-Diaz, Caitlin M. Carroll, Stephen M. Day, John Grizzanti, Thomas E. Mahan, James A. Snipes, Timothy E. Orr, Joseph P. Culver, Maria S. Remedi, Colin G. Nichols, Celeste M. Karch, Laura A. Cox, Debra I. Diz, Adam Q. Bauer, David M. Holtzman
bioRxiv 2021.08.11.455969; doi: https://doi.org/10.1101/2021.08.11.455969

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