钾通道
Kir6.2
糖尿病前期
神经科学
淀粉样蛋白(真菌学)
ATP敏感性钾离子通道
阿尔茨海默病
医学
内分泌学
内科学
糖尿病
疾病
2型糖尿病
化学
生物
病理
蛋白质亚单位
生物化学
基因
格列本脲
作者
John Grizzanti,William R. Moritz,Morgan C. Pait,Molly Stanley,Sarah D. Kaye,Christie L. Carroll,Nicholas J. Constantino,Lily J. Deitelzweig,James A. Snipes,Derek Kellar,Emily Caesar,Ryan J. Pettit-Mee,Marc Day,Jonathon P. Sens,Noelle I. Nicol,Jasmeen Dhillon,Marı́a S. Remedi,Drew D. Kiraly,Celeste M. Karch,Colin G. Nichols,David M. Holtzman,Shannon L. Macauley
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2023-05-02
卷期号:8 (10)
被引量:3
标识
DOI:10.1172/jci.insight.162454
摘要
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.
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