Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease

Abstract

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

Keywords: Alzheimer’s disease; Apolipoprotein E4; amyloid-β; meningeal lymphatic vessels; tau.

Fig. 1

The structure and location of dorsal and basal mLVs. Schematic images of dorsal and basal mLVs tracking along the dural sinus with differences in structures, branches, lumen diameter, and lymphatic valves. Dorsal mLVs travel along the superior sagittal sinus (SSS) and transverse sinus (TS). The lumen is primarily a discontinuous vascular structure, with a small diameter and no valves. Basal mLVs are located near the subarachnoid space (SAS) and run along the petrosal sinus (PSS) and sigmoid sinus (SS). The lumen is primarily a continuous vascular structure with a large diameter and lymphatic valves.

Fig. 2

Overview of the transport of CSF and ISF through meningeal lymphatic vessels. Cerebrospinal fluid (CSF) is transported within a specialized perivascular network that helps to remove metabolic products from the central nervous system to the peripheral circulation system. A) CSF transport in the glymphatic pathway through periarterial inflow and perivenous outflow. CSF in the subarachnoid space flows into the brain through the perivascular space of the perforating arteries, which is called the periarterial inflow. Through glymphatic CSF/interstitial fluid (ISF) exchange in the brain parenchyma, metabolic wastes such as Aβ and cytokines are excreted toward the perivenous space. These products ultimately reach deep cervical lymph nodes (dCLNs) and peripheral circulation through meningeal lymphatic vessels. B) Magnified schematic illustration of CSF inflow and ISF outflow to the subarachnoid space along the periarterial and perivenous space.