Abstract
Recent studies have revealed significant contributions of lymphatic vessels (LVs) to vital functions of the brain, especially related to clearance of waste from the brain and immune responses in the brain. These studies collectively indicate that enhancing the functions of LVs may improve brain functions during brain aging and in Alzheimer’s disease (AD) where LV functions are impaired. However, it is currently unknown whether this enhancement can be achieved using small molecules. We have previously shown that a widely used Chinese herbal medicine Xueshuantong (XST) significantly improves functions and reduces pathology in AD transgenic mice associated with elevated cerebral blood flow (CBF). Here, we show that XST partially rescues deficits in lymphatic structures, improves clearance of amyloid-β (Aβ) from the brain, and reduces the inflammatory responses in the serum and brains of transgenic AD mice. In addition, we showed that this improvement in the lymphatic system occurs independently of elevated CBF, suggesting independent modulation and limited interaction between blood circulation and lymphatic systems. Moreover, XST treatment leads to a significant increase in GLT-1 level and a significantly lower level of MMP-9 and restores AQP4 polarity in APP/PS1 mice. These results provide the basis for further exploration of XST to enhance or restore LV functions, which may be beneficial to treat neurodegenerative diseases or promote healthy aging.
Highlights
New drugs are urgently needed for Alzheimer’s disease (AD), especially those that do not target amyloid-β (Aβ) and tau since a variety of those drugs have shown minimal effectiveness in the clinical trials (Polanco et al, 2018; Zhu et al, 2019)
We found a significant reduction in the Lyve-1+ area in the APP/PS1 mice compared to WT mice (Figures 1C,E; p < 0.01), while these areas were significantly larger in XST-treated mice (Figures 1C,E; p < 0.01)
In the sagittal sinus (SSS) region of both APP/PS1 and WT mice (Figure 1B; CD31+), we found a significant reduction in the diameters of CD31+ blood vessels (BVs) in APP/PS1 mice compared to WT mice (Figures 1B,F; p < 0.05), while XST-treated group exhibited significantly larger diameters in both APP/PS1 and WT mice (Figures 1B,F; p < 0.05)
Summary
New drugs are urgently needed for Alzheimer’s disease (AD), especially those that do not target amyloid-β (Aβ) and tau since a variety of those drugs have shown minimal effectiveness in the clinical trials (Polanco et al, 2018; Zhu et al, 2019). Limited evidence suggests that improving CBF leads to improved functions and reduced pathology in AD transgenic mice (Kisler et al, 2017; Bracko et al, 2019). Recent studies highlight the important contributions of lymphatic vessels (LVs) to the impaired brain functions in aging and in AD (van der Kleij et al, 2018; Da Mesquita et al, 2018a; Da Mesquita et al, 2018b). The ability to correct or compensate for the deficits in LV structure and functions and restore the brain clearance system is of great interest and importance for promoting healthy aging and treating neurodegenerative diseases (such as AD). No small molecule compound is known to modulate the structure/function of LVs. Given the importance of the lymphatic system, such small molecules may have significant therapeutic potentials
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