Impaired cerebral microvascular reactivity and endothelial SK channel activity in a streptozotocin-treated mouse model of Alzheimer's disease

作者：Hang Xing, Shawn Kant, Meghamsh Kanuparthy, Dwight D. Harris, Christopher Stone, Mark Broadwin, Zhi‐Qi Zhang, Elena Pearson, Jiayu Hu, Ava Sauer, Amy M. Princiotto, Elizabeth O. Harrington, Suzanne M. de la Monte, Frank W. Sellke, Jun Feng · 发表于：Journal of Alzheimer s Disease · 年份：2025 · DOI：10.1177/13872877241309120 · 被引用次数：4 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Barrier Structure and Function Studies

Background Alzheimer's disease (AD) is a complex neurodegenerative disease marked by increased amyloid-β (Aβ) deposition, tau hyperphosphorylation, impaired energy metabolism, and chronic ischemia-type injury. Cerebral microvascular dysfunction likely contributes to AD pathology, but its precise pathogenic role has been poorly defined. Objective To examine microvascular reactivity to endothelium-dependent vasodilators and small conductance calcium-activated potassium (SK) channel activity in an intracerebral streptozotocin (STZ)-induced AD mouse model. Methods Control and STZ-AD mice underwent Morris Water Maze and Barnes testing, after which cerebral microvascular and brain microvascular endothelial cells (MBMECs) were dissected to assess microvascular reactivity, responses to SK channel activator NS309, and ion-channel current recordings using whole-cell patch clamp methodology. Control mouse cerebral microvascular and human brain microvascular endothelial cells (HBMECs) were treated with soluble Aβ 1–42 peptide to characterize microvascular reactivity and endothelial potassium currents. Results STZ-AD mice exhibited impaired performance vs control mice in behavioral testing. STZ-AD mice also exhibited diminished cerebral microvascular responsiveness and MBMECs potassium current augmentation in response to NS309 compared with control mice. Incubation of control mouse cerebral micro-vessels and HBMECs with soluble Aβ (1 µM) for 2 h attenuated relaxation responses to NS309 an...