Udo Mariana Sayuri Berto, Zaccarelli-Magalhães Julia, Clemons Garrett Alan, Citadin Cristiane Teresinha, Langman Julia, Smith Drew James, Matuguma Luiz Henrique, Tesic Vesna, Lin Hung Wen
Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA.
Department of Biomedical Science, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
Geroscience. 2025 Jan 22. doi: 10.1007/s11357-025-01526-8.
Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 6.2 million Americans aged 65 and older, particularly women. Along with AD's main hallmarks (formation of β-amyloid plaques and tau neurofibrillary tangles), there are vascular alterations that occurs in AD pathology. Adenosine A2 receptor (AR) is one of the key factors of brain vascular autoregulation and is overexpressed in AD patients. Our previous findings suggest that protein arginine methyltransferase 4 (PRMT4) is overexpressed in AD, which leads to decrease in cerebral blood flow in aged female 3xTg mice. We aimed to investigate the mechanism behind AR signaling in the regulation of brain perfusion and blood-brain barrier integrity in age and sex-dependent 3xTg mice, and if it is related to PRMT4. Istradefylline, a highly selective AR antagonist, was used to modulate AR signaling. Aged female 3xTg and C57BL/6 J mice were evaluated for brain perfusion (via laser speckle) and cognitive function (via open field, T-maze and novel object recognition). Our results suggest that modulation of AR signaling in aged female 3xTg increased cerebral perfusion by decreasing PRMT4 expression, restored the levels of APP and tau, maintained blood-brain barrier integrity by maintaining the expression of tight junction proteins, and preserved functional learning/memory.
阿尔茨海默病（AD）是一种神经退行性疾病，影响着超过620万65岁及以上的美国人，尤其是女性。除了AD的主要特征（β-淀粉样蛋白斑块和tau神经原纤维缠结的形成）外，AD病理学中还存在血管改变。腺苷A2受体（AR）是脑血管自动调节的关键因素之一，在AD患者中过度表达。我们之前的研究结果表明，蛋白精氨酸甲基转移酶4（PRMT4）在AD中过度表达，这导致老年雌性3xTg小鼠脑血流量减少。我们旨在研究AR信号在年龄和性别依赖性3xTg小鼠中调节脑灌注和血脑屏障完整性的机制，以及它是否与PRMT4有关。使用高度选择性AR拮抗剂异喹啉治疗来调节AR信号。对老年雌性3xTg和C57BL/6 J小鼠进行脑灌注（通过激光散斑）和认知功能（通过旷场试验、T迷宫和新物体识别）评估。我们的结果表明，调节老年雌性3xTg小鼠的AR信号可通过降低PRMT4表达来增加脑灌注，恢复APP和tau的水平，通过维持紧密连接蛋白的表达来维持血脑屏障的完整性，并保留功能性学习/记忆。
