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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

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 3

Pharmacological manipulation of KATP channels blocks hyperglycemia-induced increases in ISF Aβ.

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Pharmacological manipulation of KATP channels blocks hyperglycemia-induc...
(A) In 18-month-old APP/PS1 mice, glucose clamps increase ISF Aβ. However, when diazoxide, a KATP agonist, is given via reverse microdialysis during hyperglycemia, the increase in ISF Aβ is blocked (38.84% ± 3.5% vs. 9.33% ± 2.1% increase). (B) Treatment with diazoxide decreased hippocampal ISF lactate in 18-month-old APP/PS1 mouse brains during hyperglycemia, suggesting decreased neuronal activity coincides with decreased ISF Aβ (11.8% ± 3.6% vs. –4.043% ± 3.4%). Data represent mean ± SEM. For all analyses, n = 6–7 mice/group, *P < 0.05, ***P < 0.001 using 2-way ANOVA.
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