Xing Hang, Kant Shawn, Kanuparthy Meghamsh, Harris Dwight, Stone Christopher, Broadwin Mark, Zhang Zhiqi, Pearson Elena, Hu Jiayu, Sauer Ava, Princiotto Amy, Harrington Elizabeth O, de la Monte Suzanne M, Sellke Frank, Feng Jun
Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
Vascular Research Laboratory, Providence VA Medical Center, Alpert Medical School of Brown University, Providence, RI, USA.
J Alzheimers Dis. 2025 Feb;103(4):1112-1125. doi: 10.1177/13872877241309120. Epub 2025 Jan 10.
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.
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.
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 peptide to characterize microvascular reactivity and endothelial potassium currents.
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 and diminished NS309-sensitive endothelial potassium currents.
STZ-AD mice exhibited impaired microvascular relaxation responses to endothelium-dependent vasodilators; SK/IK channel dysfunction may be involved in the mechanism of this impairment. Acute treatment with Aβ produced dysregulated cerebrovascular endothelial SK/IK channels. Further elucidation of the role of microvascular dysfunction in AD is needed to prevent the chronic ischemia-type injury that contributes to cognitive decline.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其特征为淀粉样β蛋白（Aβ）沉积增加、tau蛋白过度磷酸化、能量代谢受损以及慢性缺血样损伤。脑微血管功能障碍可能参与AD的病理过程，但其确切的致病作用尚未明确。
在脑内注射链脲佐菌素（STZ）诱导的AD小鼠模型中，检测微血管对内皮依赖性血管舒张剂的反应性以及小电导钙激活钾（SK）通道活性。
对对照组和STZ-AD小鼠进行莫里斯水迷宫和巴恩斯测试，之后解剖脑微血管和脑微血管内皮细胞（MBMECs），以评估微血管反应性、对SK通道激活剂NS309的反应以及使用全细胞膜片钳技术记录离子通道电流。用可溶性Aβ肽处理对照小鼠脑微血管和人脑血管内皮细胞（HBMECs），以表征微血管反应性和内皮钾电流。
与对照小鼠相比，STZ-AD小鼠在行为测试中表现受损。与对照小鼠相比，STZ-AD小鼠对NS309的脑微血管反应性降低，MBMECs钾电流增强减弱。用可溶性Aβ（1 μM）孵育对照小鼠脑微血管和HBMECs 2小时，可减弱对NS309的舒张反应，并降低NS309敏感的内皮钾电流。
STZ-AD小鼠对内皮依赖性血管舒张剂的微血管舒张反应受损；SK/IK通道功能障碍可能参与了这种损伤机制。Aβ急性处理导致脑血管内皮SK/IK通道失调。需要进一步阐明微血管功能障碍在AD中的作用，以预防导致认知衰退的慢性缺血样损伤。
