中樞神經系統（CNS）曾被認為是無淋巴管的器官。根據近期動物研究的結果，證實中樞神經系統中淋巴系統的存在。中樞神經系統中有兩條主要的淋巴途徑：神經膠細胞類淋巴途徑和腦膜淋巴 (mLym)系統。腦膜淋巴系統可以將大分子、液體和廢物從大腦運送到頸部淋巴結 (CLNs)。研究表明，該系統的結構和功能在老化過程中逐漸惡化。由於老化是阿茲海默症 (AD) 的主要危險因素，因此值得詳細探討這個該系統與阿茲海默症發病機制之間的關係。細胞外澱粉樣蛋白-β (Aβ) 胜肽累積和聚集導致澱粉樣斑塊沉積被認為是阿茲海默症發病機制的標誌。運動被認為是一種增強學習和記憶功能並延緩阿茲海默症發病機制的有效策略。然而，運動是否會影響腦膜淋巴系統的結構和功能尚不清楚。首先，我們開發了一種新技術，透過以奈米粒子作為顯影劑的高頻超音波成像來即時監測腦膜淋巴系統的功能。該技術透過淋巴管結紮和使用 visudyne 和光轉換進行腦膜淋巴管消融得到了驗證。與3個月大的阿茲海默症基因轉殖小鼠 (5xFAD)小鼠相比，6 個月大的5xFAD小鼠，即澱粉樣蛋白斑塊沉積期，顯示出腦膜淋巴系統功能下降，包括腦脊髓液從側腦室到深頸部淋巴結的流量和速度。這些變化在 6 個月大的野生型小鼠中未見。 腦膜淋巴系統淋巴管的直徑和麵積，以及腦膜（LYVE-1 和 VEGFR3）和大腦（VEGF-C）中淋巴管相關基因的表達均減少。此外，6 個月大的 5xFAD 小鼠的學習和記憶能力表現受損。將傳入深頸部淋巴結的淋巴管結紮加速了腦部的澱粉樣變性。從3個月大開始進行3個月的跑步鍛煉，增加了背側和基底區域腦膜淋巴系統中淋巴管的大小和功能，以及LYVE-1、VEGFR3和VEGF-C基因的表達。這些小鼠的澱粉樣變性數量減少，學習和記憶能力也得到改善。體外研究表明，Aβ 寡聚物降低了人類真皮淋巴內皮細胞中的 VEGFR3 基因表達，而運動小鼠的血清和細胞外囊泡則抑制了 A 寡聚物誘導的 VEGFR3 下調。總之，跑步運動可以透過增強 腦膜淋巴系統的功能，成為另一種延緩澱粉樣變性的非藥物治療策略。

The central nervous system (CNS) was thought to be the lymphatic vessel-free organ. Recently, based on the results from animal studies, the lymphatic system in the CNS has been demonstrated. There are two main CNS lymphatic pathways: glymphatic route and meningeal lymphatic (mLym) vasculature. The mLym system can transport macromolecules, fluid, and waste products out from the brain to the cervical lymph nodes (CLNs). It has been shown that the structure and function of this system gradually deteriorated during aging. Because aging is the major risk factor for Alzheimer's disease (AD), the relationship between this system and AD pathogenesis deserves explored in detail. Extracellular accumulation and aggregation of amyloid-β (Aβ) peptides leading to deposition of amyloid plaques has been considered as the hallmark of AD pathogenesis. Exercise has been implicated as a useful strategy to enhance learning and memory function and delay AD pathogenesis. However, whether exercise can affect the structure and function of the meningeal lymphatic system is unclear. Initially, we developed a new technique to real-time monitor the function of the mLym system via the high-frequency ultrasound imaging with nanoparticles as the contrast agent. This technique was validated by lymphatic vessel ligation and mLym vessel ablation with visudyne and photoconversion. Transgenic mice of AD (5xFAD) at 6 months of ages, a period of the amyloid plaque deposition, showed a reduction of mLym function, including the flow volume and speed of the cerebrospinal fluid from the lateral ventricles to the deep CLNs, compared to 3-month-old 5xFAD mice. These changes were not observed in 6-month-old wild-type mice. The diameter and the area of mLym vessels, as well as the expression of lymphatic vessel-related genes in the meninges (LYVE-1 and VEGFR3) and in the brain (VEGF-C) were reduced. Moreover, learning and memory performances were impaired in 6-month-old 5xFAD. Amyloidosis in the brain was accelerated by ligation of the afferent lymphatic vessels to the deep CLNs. Three months of running exercise starting from 3 months old increased the size and function of mLym vessels in both dorsal and basal areas, as well as the expression of LYVE-1, VEGFR3, and VEGF-C genes. The amounts of amyloidosis were reduced, and the learning and memory abilities were improved in these mice. In vitro study showed that Aβ oligomers decreased the VEGFR3 gene expression in human dermal lymphatic endothelial cells, whereas serum and extracellular vesicles from exercised mice inhibited the Aβ oligomer-induced downregulation of VEGFR3. In conclusion, running exercise can be an alternative non-pharmaceutical therapeutic strategy for delaying amyloidosis by enhancing the function of mLym system.

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