Kir6.2-containing K ATP channels are necessary for glucose dependent increases in amyloid-beta and Alzheimer’s-related pathology

ABSTRACT Increased neuronal excitability contributes to amyloid-β (Aβ) production and aggregation in the Alzheimer’s disease (AD) brain. Previous work from our lab demonstrated that hyperglycemia, or elevated blood glucose levels, increased brain excitability and Aβ release potentially through inward rectifying, ATP-sensitive potassium (K ATP ) channels. K ATP channels are present on several different cell types and help to maintain excitatory thresholds throughout the brain. K ATP channels are sensitive to changes in the metabolic environment, which are coupled to changes in cellular excitability. Therefore, we hypothesized that neuronal K ATP channels are necessary for the hyperglycemic-dependent increases in extracellular Aβ and eliminating K ATP channel activity will uncouple the relationship between metabolism, excitability, and Aβ pathology. First, we demonstrate that Kir6.2/ KCNJ11 , the pore forming subunits, and SUR1/ ABCC8 , the sulfonylurea receptors, are predominantly expressed on excitatory and inhibitory neurons in the human brain and that cortical expression of KCNJ11 and ABCC8 change with AD pathology in humans and rodent models. Next, we crossed APP/PS1 mice with Kir6.2 -/- mice, which lack neuronal K ATP channel activity, to define the relationship between K ATP channels, Aβ, and hyperglycemia. Using in vivo microdialysis and hyperglycemic clamps, we explored how acute elevations in peripheral blood glucose levels impacted hippocampal interstitial fluid (ISF) glucose, lactate, and Aβ levels in APP/PS1 mice with or without K ATP channels. Kir6.2+/+, APP/PS1 mice and Kir6.2-/-, APP/PS1 mice were exposed to a high sucrose diet for 6 months to determine the effects of chronic hyperglycemia on Aβ deposition. We found that elevations in blood glucose levels correlate with increased ISF Aβ, amyloidogenic processing of amyloid precursor protein (APP), and amyloid plaque pathology in APP/PS mice with intact K ATP channels. However, neither acute hyperglycemia nor chronic sucrose overconsumption raised ISF Aβ or increased Aβ plaque burden in APP/PS1 mice lacking Kir6.2-K ATP channel activity. Mechanistic studies demonstrate ISF glucose not only correlates with ISF Aβ but also ISF lactate. Without K ATP channel activity, ISF lactate does not increase during hyperglycemia, which correlates with decreased monocarboxylate transporter 4 (MCT4) expression, a lactate transporter responsible for astrocytic lactate release. This suggests that K ATP channel activity regulates ISF lactate during hyperglycemia, which is important for Aβ release and aggregation. These studies identify a new role for Kir6.2-K ATP channels in Alzheimer’s disease pathology and suggest that pharmacological antagonism of Kir6.2-K ATP channels holds therapeutic promise in reducing Aβ pathology, especially in diabetic and prediabetic patients.