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

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

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 2

Modulation of hippocampal KATP channels affects ISF Aβ and lactate in vivo.

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Modulation of hippocampal KATP channels affects ISF Aβ and lactate in vi...
(A) Glibenclamide, a KATP antagonist, was given via reverse microdialysis and increased ISF Aβ in a dose-dependent manner, with a maximal increase of 36.2% ± 3.2% at 100 μM. The left panel represents a time course of the 100 μM dose, while the right demonstrates the dose-dependent effects of glibenclamide. (B) ISF lactate increased in a dose-dependent manner, with a maximal increase of 73.3-5% ± 19.8%. The left panel represents a time course of the 100 μM dose, while the right illustrates the dose-dependent effects of glibenclamide. (C) Diazoxide, a KATP agonist, did not alter ISF Aβ levels. The left panel demonstrates a time course of the 300 μM dose of diazoxide, where the right shows that diazoxide does not affect ISF Aβ at any dose. (D) Diazoxide (300 μM) decreased ISF lactate by 22.5% ± 4.3% after administration. The left panel demonstrates the time course of the 300 μM dose of diazoxide, while the right shows a dose response of diazoxide. Data represent mean ± SEM. For all analyses, n = 5–7 mice/group per glibenclamide dose and n = 4–5 mice/group per diazoxide dose. *P < 0.05, **P < 0.01, ***P < 0.001 using a 1-way ANOVA.