Coordination of brain fluid transport, proteostasis, and vascular function is essential for neural homeostasis, yet whether extracranial lymphatic outflow can actively shape central neurovascular states remains poorly understood. Here, we identify a lymphatic-choroid plexus signaling axis through which extracranial drainage regulates intracranial proteostatic and vascular remodeling. Using cervical lymphatic-venous anastomosis (LVA) as a gain-of-function approach in an Alzheimer's disease (AD) rat model, we show that enhancement of extracranial lymphatic outflow rapidly stabilizes cerebrospinal fluid-associated ventricular dynamics, selectively reduces oligomeric amyloid-beta burden, and improves locomotor performance. Single-cell transcriptomic profiling further reveals broad remodeling of the hippocampal neurovascular niche, marked by attenuation of inflammatory microglial programs and reinforcement of vascular communication networks. Mechanistically, LVA induces a secretory response in choroid plexus epithelial (CPE) cells characterized by co-upregulation of clusterin (CLU) and vascular endothelial growth factor (VEGF). This CLU-VEGF epithelial program links amyloid chaperoning to microvascular remodeling, accompanied by increased choroid plexus microvessel density and vascular caliber, preserved cerebral perfusion, and restoration of neurovascular homeostasis. Together, these findings define the choroid plexus as a biomechanical-molecular transducer that connects extracranial lymphatic drainage with central proteostasis and vascular regulation. The lymphatic-choroid plexus axis provides a new framework for understanding how peripheral fluid drainage shapes brain homeostasis and suggests a novel mechanism of action for treating neurodegenerative diseases.
Guo, P., Pei, X.
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