Yuanzhi powder facilitated Aβ clearance in APP/PS1 mice: Target to the drainage of glymphatic system and meningeal lymphatic vessels

Yuanzhi Powder (YZP) is a classical Chinese medicine prescription, which is suitable for the treatment of dementia by "dispelling phlegm and opening orifice". The therapeutic efficacy of YZP on Alzheimer's disease (AD) has been previously reported in our work. However, it remains unclear whether the neuroprotective effect of YZP is linked to β-amyloid(Aβ) clearance through cerebral lymphatic drainage.The aim was to determine the protective efficacy of YZP against AD and investigate the potential mechanism for eliminating excessive Aβ deposition.APP/PS1 mice were divided into four groups of 8 mice each: APP/PS1 group, DONE group, L-YZP group, and H-YZP group. Additionally, 8 wild-type littermates were assigned to the control group (WT group). After 8 weeks of consecutive intragastric administration, behavioral tests, including the open field test, novel object recognition test and Morris Water Maze test, were employed to assess the cognitive abilities of all groups of mice. Nissl staining, immunohistochemistry, and western blotting were utilized to evaluate clearance of excessive Aβ deposition and pathological changes. Furthermore, immunofluorescence was applied to visualize the drainage of the cerebral lymphatic system after fluorescent tracer injection in the cisterna magna.The administration of YZP significantly attenuated cognitive deficits, cleared excessive Aβ deposition, and improved pathological damage in APP/PS1 mice. Furthermore, YZP effectively enhanced glymphatic system drainage by restoring AQP4 polarization and inhibiting reactive astrogliosis. Additionally, YZP facilitated the drainage of meningeal lymphatic vessels (MLVs) by augmenting their diameter and coverage. Lastly, YZP promoted the elimination of Aβ from the brain to deep cervical lymph nodes.The administration of YZP may ameliorate the cognitive deficits and pathological damage in APP/PS1 mice by effectively clearing excessive Aβ deposition. The underlying mechanisms potentially involve Aβ clearance through the cerebral lymphatic system, which includes the glymphatic system and MLVs.