英国伦敦大学学院David Attwell研究小组发现，抑制阿尔茨海默病模型小鼠中的Ca²⁺通道可使周细胞松弛，改善脑血流，减少免疫细胞停滞和缺氧。2024年9月18日，国际知名学术期刊《自然—神经科学》发表了这一成果。

利用激光多普勒、散斑血流法和磁共振成像进行体内双光子成像，该团队发现Ca²⁺通过L型电压门控钙通道(CaVs)进入控制周细胞的收缩张力。在AD模型小鼠中，该课题组发现，整个毛细血管床的周细胞是免疫活性氧(ROS)诱发，和周细胞内钙浓度([Ca²⁺]_i)介导的微血管血流减少的关键驱动因素。

在疾病进展早期用尼莫地平阻断CaVs可改善脑血流量(CBF)，减少周细胞体细胞的白细胞停滞，减轻脑缺氧。β淀粉样蛋白(Aβ)引起的人皮质组织周细胞收缩，也被CaV阻断大大减少。在AD早期降低周细胞[Ca²⁺]_i可能提供一种治疗策略，以增强AD患者的大脑能量供应和可能的认知功能。

研究人员表示，在阿尔茨海默病(AD)的早期，周细胞收缩毛细血管，增加其液压阻力并导致免疫细胞滞留，从而减少脑血流量(CBF)。目前缺乏减轻AD患者周细胞介导的收缩的治疗方法。

附：英文原文

Title: Inhibiting Ca2+ channels in Alzheimer’s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia

Author: Korte, Nils, Barkaway, Anna, Wells, Jack, Freitas, Felipe, Sethi, Huma, Andrews, Stephen P., Skidmore, John, Stevens, Beth, Attwell, David

Issue&Volume: 2024-09-18

Abstract: Early in Alzheimer’s disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca2+]i)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca2+]i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD.

DOI: 10.1038/s41593-024-01753-w

Source: https://www.nature.com/articles/s41593-024-01753-w