Wang Ni-Ya, Li Jin-Nan, Liu Wei-Lin, Huang Qi, Li Wen-Xing, Tan Ya-Hong, Liu Fang, Song Zi-Hua, Wang Meng-Yue, Xie Ning, Mao Rong-Rong, Gan Ping, Ding Yu-Qiang, Zhang Zhi, Shan Bao-Ci, Chen Li-Dian, Zhou Qi-Xin, Xu Lin
CAS Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-SU Joint Laboratory of Animal Model and Drug Development, and Laboratory of Learning and Memory, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, 650223, China.
Kunming College of Life Sciences, University of the Chinese Academy of Sciences, Kunming, 650223, China.
Neurotherapeutics. 2021 Apr;18(2):1064-1080. doi: 10.1007/s13311-021-01024-7. Epub 2021 Mar 30.
Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.
脑毛细血管通过向大脑供应氧气和其他营养物质并清除大脑中的代谢废物，对认知功能至关重要。最近的研究表明，β-淀粉样蛋白（Aβ）寡聚体通过内皮素-1（ET1）对内皮素1受体A（ETRA）的介导作用触发脑毛细血管收缩，这可能会加剧Aβ斑块沉积，而Aβ斑块沉积是阿尔茨海默病（AD）的主要病理生理学特征。然而，脑毛细血管的变化是否因果性地参与AD的病理生理学过程，仍然缺乏直接证据。相对于年龄匹配的阴性同窝小鼠，我们使用AD的APP/PS1小鼠模型（AD小鼠）发现，海马毛细血管的密度和直径在4至7个月大时降低，而Aβ斑块沉积和空间记忆缺陷在7个月大时出现。值得注意的是，向AD小鼠海马注射ET1会在5个月大时诱导早期Aβ斑块沉积。相反，用阿魏酸针对ETRA进行治疗以抵消ET1介导的血管收缩30天，可防止AD小鼠在7个月大时海马毛细血管密度和直径的降低，以及改善Aβ斑块沉积和空间记忆缺陷。因此，这些数据表明，海马毛细血管密度和直径的降低对于在早期引发Aβ斑块沉积和空间记忆缺陷至关重要，这意味着开发新的疗法来阻止或治愈AD中的记忆衰退。
