Jiawei Xionggui Decoction promotes meningeal lymphatic vessels clearance of β-amyloid by inhibiting arachidonic acid pathway

•Jiawei Xionggui Decoction (JWXG) is the formula developed by our team that has been authorized by the invention patent in China, which has shown good results and safety in alleviating a variety of cognitive impairment models.•As a newly discovered anatomical structure, the physiological function of meningeal lymphatic vessels (mLVs) is mainly involved in the regulation of immune privilege and metabolic waste clearance mechanism in the central nervous system. We confirmed that JWXG was associated with improved mLVs drainage dysfunction in AD with alleviating AD cognitive impairment.•Further non-targeted metabolomics analysis revealed the main pathways of JWXG clearance mechanism in AD mice with mLVs drainage dysfunction. Excessive neuroinflammation induced by arachidonic acid is a key cause of pathological deterioration in AD mice with mLVs drainage dysfunction. 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 inhi