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Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo
Shannon L. Macauley, … , Courtney L. Sutphen, David M. Holtzman
Shannon L. Macauley, … , Courtney L. Sutphen, David M. Holtzman
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2463-2467. https://doi.org/10.1172/JCI79742.
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Brief Report Neuroscience Article has an altmetric score of 265

Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

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Abstract

Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques — glucose clamps and in vivo microdialysis — as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (KATP) channels mediated the response to elevated glucose levels, as pharmacological manipulation of KATP channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that KATP channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels.

Authors

Shannon L. Macauley, Molly Stanley, Emily E. Caesar, Steven A. Yamada, Marcus E. Raichle, Ronaldo Perez, Thomas E. Mahan, Courtney L. Sutphen, David M. Holtzman

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Figure 1

Hyperglycemia increases ISF glucose and Aβ levels in the APP/PS1 hippocampus in vivo.

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Hyperglycemia increases ISF glucose and Aβ levels in the APP/PS1 hippoca...
(A) Blood glucose levels in 3-month-old APP/PS1 mice (n = 6–8 mice/group) during fasted baseline and hyperglycemic clamp. (B) ISF glucose levels increased from 0.158 ± 0.004 to 0.306 ± 0.011 mmol/l during hyperglycemia in 3-month-old APP/PS1 mice (n = 6–8 mice/group). (C) Hyperglycemia increased ISF Aβ levels by 24.5% ± 3.8% in 3-month-old APP/PS1 mice during and after clamp (n = 6–7 mice/group). (D) ISF Aβ correlates with ISF glucose during hyperglycemia (n = 6 mice, Pearson’s r = 0.6032; P < 0.01). (E) ISF glucose levels increased from 0.153 ± 0.003 to 0.397 ± 0.0149 mmol/l during hyperglycemia in 18-month-old APP/PS1 mice (n = 6–7 mice/group). (F) Hyperglycemia increased ISF Aβ levels by 38.8% ± 5.3% in 18-month-old APP/PS1 mice, during and after glucose clamps (n = 6–7 mice/group). (G) Hyperglycemia increases ISF lactate, a marker of neuronal activity (n = 7 mice/group). (H) Compound E decreases ISF Aβ during hyperglycemia and does not alter ISF Aβ half-life, demonstrating hyperglycemia alters Aβ production, not Aβ clearance. Data represent mean ± SEM. Significance denoted *P < 0.05, **P < 0.01, and ***P < 0.001 using 2-way ANOVA (C and F) or Student’s t tests (A, B, E, G, and H).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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