KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology
John Grizzanti, William R. Moritz, Morgan C. Pait, Molly Stanley, Sarah D. Kaye, Caitlin M. Carroll, Nicholas J. Constantino, Lily J. Deitelzweig, James A. Snipes, Derek Kellar, Emily E. Caesar, Ryan J. Pettit-Mee, Stephen M. Day, Jonathon P. Sens, Noelle I. Nicol, Jasmeen Dhillon, Maria S. Remedi, Drew D. Kiraly, Celeste M. Karch, Colin G. Nichols, David M. Holtzman, Shannon L. Macauley
John Grizzanti, William R. Moritz, Morgan C. Pait, Molly Stanley, Sarah D. Kaye, Caitlin M. Carroll, Nicholas J. Constantino, Lily J. Deitelzweig, James A. Snipes, Derek Kellar, Emily E. Caesar, Ryan J. Pettit-Mee, Stephen M. Day, Jonathon P. Sens, Noelle I. Nicol, Jasmeen Dhillon, Maria S. Remedi, Drew D. Kiraly, Celeste M. Karch, Colin G. Nichols, David M. Holtzman, Shannon L. Macauley
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Research Article Aging Neuroscience

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology

Abstract

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2–/– mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.

Authors

John Grizzanti, William R. Moritz, Morgan C. Pait, Molly Stanley, Sarah D. Kaye, Caitlin M. Carroll, Nicholas J. Constantino, Lily J. Deitelzweig, James A. Snipes, Derek Kellar, Emily E. Caesar, Ryan J. Pettit-Mee, Stephen M. Day, Jonathon P. Sens, Noelle I. Nicol, Jasmeen Dhillon, Maria S. Remedi, Drew D. Kiraly, Celeste M. Karch, Colin G. Nichols, David M. Holtzman, Shannon L. Macauley

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Figure 9

Alterations in lactate metabolism and transport because of the interaction among Aβ, KATP channels, and a high-sucrose diet.

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Alterations in lactate metabolism and transport because of the interacti...
(A) Simplified schematic of glucose uptake, lactate production, and lactate transport compartmentalized in astrocytes and neurons. Astrocytes take up glucose via Glut1 and process it glycolytically (e.g., Hk1 and Gapdh). Pyruvate is converted to lactate via Ldha and released extracellularly via Mct4. Lactate uptake into neurons is mediated by Mct2, where it is converted back to pyruvate via Ldhb for use in mitochondrial respiration and oxidative phosphorylation. (B) Female Kir6.2+/+ APP/PS1 mice on a high-sugar diet had decreased Glut1 and Mct2 expression compared with WT, suggesting decreased glucose uptake in astrocytes and decreased lactate uptake in neurons, while displaying increased Hk1 expression, suggesting increased glycolysis. Kir6.2–/– APP/PS1 mice on a high-sugar diet had an opposing phenotype, where Mct2 expression increased, Pdha1 increased, and Mct4 decreased, suggesting less astrocytic lactate release, conserved neuronal lactate uptake, and preserved mitochondrial respiration. Kir6.2+/+ APP/PS1 mice alone displayed decreased Pdha1, Ldha, and Ldhb expression, which was not mirrored in Kir6.2–/– APP/PS1 mice. All relationships were analyzed via 1-way ANOVA with Tukey’s post hoc analysis (n = 7–11). All data were analyzed via 1-way ANOVA and represented as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.