Non-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer's disease-associated pathology and cognition in miceted pathology and cognition in mice

Meningeal lymphatic vessels (mLVs) have been shown to be involved in amyloid beta (Aß) clearance, which is considered as a potential therapeutic target for Alzheimer's disease (AD). In this study, based on the superficial spatial distribution of mLVs, a near-infrared light is employed to modulate lymphatic drainage, significantly improving cognition of both aged and AD (5xFAD and APP/PS1) mice, and alleviating AD-associated pathology by reducing Aß deposition, neuroinflammation and neuronal damage. Furthermore, transmission electron microscopy imaging and RNA sequencing data indicate amelioration of mitochondrial metabolism and cellular junction of meningeal lymphatic endothelial cells (mLECs) by light modulation. These studies collectively suggest that near-infrared light treatment can improve cognitive function by strengthening scavenging ability of mLVs through restoring mLEC function. In conclusion, lymphatic drainage potentiation by light promotes pathological remission and cognitive enhancement in aging and AD mouse models, which offers a potential amelioration strategy for neurodegenerative diseases. Overall design: Comparative gene expression profiling analysis of RNA-seq data for hippocampus, meninges and meningeal lymphatic endothelial cells of 6-month 5xFAD male mice receiving light treatment vs. no-light treatment, as well as 6-month 5xFAD male mice vs. 6-month wild type mice.