State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Phytomedicine. 2024 Dec;135:156041. doi: 10.1016/j.phymed.2024.156041. Epub 2024 Sep 12.
Alzheimer's disease (AD) is an aging-associated form of dementia characterized by the pathological deposition of toxic misfolded proteins in the central nervous system (CNS), which is closely related to the clearance impairment of meningeal lymphatic vessels (mLVs). Thus, enhancement dural meningeal lymphatic drainage to remove amyloid-β (Aβ) is usually considered as a potential therapeutic target for AD.
This study aimed to investigate the mechanisms of Jiawei Xionggui Decoction (JWXG) to attenuate cognitive dificits in APP/PS1 mice with impaired meningeal lymphatic drainage.
Ligation of deep cervical lymph nodes (dcLNs) was performed to establish the mice model of the impaired meningeal lymphatic drainage in APP/PS1 mice. Cognitve behaviors and pathological morphology of mice were assessed. Cerebral blood flow (CBF) of mice was determined using Laser speckle contrast imaging analysis. Serum non-targeted metabolomics analysis was applied to decipher the mechanisms of JWXG in rescuing the impairment of mLVs, and C8-D1A cells were employed to validate in vitro.
Disruption of mLVs in APP/PS1 mice deteriorated cognitive dysfunction, accelerated Aβ burden and glia activation, accompanied by more severe neuropathological damage, CBF reduction and neuroinflammation exacerbation. Serum non-targeted metabolomics analysis indicates the increase of arachidonic acid (AA) metabolic pathway was the key contributor to the neuropathological exacerbation of dcLNs ligation APP/PS1 mice. Interestingly, clinically equivalent dose of JWXG was sufficient to restore mLVs drainage and rescue cognitive performance by inhibiting neuroinflammation depended by AA metabolic pathway in dcLNs ligation APP/PS1 mice.
Our findings establish a novel mechanism that rescue mLVs by inhibiting AA metabolic pathway to clear brain Aβ, and support JWXG as a feasible treatment strategy for AD by suppressing AA metabolic pathway to improve mLVs drainage efficiency.
阿尔茨海默病（AD）是一种与衰老相关的痴呆症，其特征是中枢神经系统（CNS）中有毒错误折叠蛋白的病理性沉积，这与脑膜淋巴管（mLV）的清除受损密切相关。因此，增强脑膜淋巴引流以清除淀粉样蛋白-β（Aβ）通常被认为是 AD 的潜在治疗靶点。
本研究旨在探讨加味雄桂汤（JWXG）通过改善脑膜淋巴引流来减轻 APP/PS1 小鼠认知障碍的机制。
通过结扎深颈淋巴结（dcLNs）建立 APP/PS1 小鼠脑膜淋巴引流受损模型。评估小鼠的认知行为和病理形态。采用激光散斑对比成像分析测定小鼠脑血流（CBF）。应用血清非靶向代谢组学分析来揭示 JWXG 恢复 mLV 功能障碍的机制，并在 C8-D1A 细胞中进行验证。
APP/PS1 小鼠 mLVs 破坏导致认知功能障碍恶化，加速 Aβ 负荷和神经胶质细胞激活，伴有更严重的神经病理学损伤、CBF 降低和神经炎症加重。血清非靶向代谢组学分析表明，花生四烯酸（AA）代谢途径的增加是 dcLNs 结扎 APP/PS1 小鼠神经病理学加重的关键因素。有趣的是，临床等效剂量的 JWXG 足以通过抑制 AA 代谢途径依赖的神经炎症来恢复 mLVs 引流并改善认知表现。
我们的研究结果建立了一种新的机制，即通过抑制 AA 代谢途径来清除脑内 Aβ，从而恢复 mLVs，支持 JWXG 通过抑制 AA 代谢途径来改善 mLVs 引流效率，作为治疗 AD 的一种可行策略。
