Abstract WP411: Identification and Characterization of Human Meningeal Lymphatics

Abstract

Late onset Alzheimer’s Disease (AD) is the most common form of dementia, affecting 40 million patients and countless families worldwide. AD is characterized by accumulation of amyloid beta (Aß) in the brain and central nervous system (CNS). A growing body of evidence indicates that while Aß production is unchanged, its clearance from the CNS is attenuated in late onset AD. Therefore, it is critical to determine how Aβ is cleared from the brain and if these processes differ in healthy and AD patients. Recently, two groups independently reported that a network of meningeal lymphatic vasculature participates in the clearance of solutes and macromolecules from the brain and cerebrospinal fluid of mice. However the presence of meningeal lymphatic vessels and their potential role in the clearance of Aß has not yet been defined in humans. Therefore, to determine if human meningeal lymphatic vessels absorb Aβ, we used immunofluorescence to examine superior sagittal sinus-associated dura mater tissue in a cohort of 21 patient samples including 6 subjects with no diagnosed dementia (control), 7 subjects with histopathologically confirmed AD, and 8 with diagnosis of mixed or other dementia. We found podoplanin (PDPN) positive, lumenized vessels in 19/21 patient samples, with 5/6 in control patients, 7/7 in AD patients and 7/8 in other or mixed dementia patients. These vessels were located in the dura mater, lateral to the superior sagittal sinus, and ranged from approximately 10 to 500 microns in diameter. Trace Aβ immunoreactivity was colocalized with podoplanin-positive vessels in 1/5 control, 1/7 AD, and 1/7 other or mixed dementia patients. Aß reactivity was found in meningeal blood vessels of 0/6 control, 1/7 AD, and 0/7 other or mixed dementia patients. To our knowledge, these data are the first to robustly support the existence of lymphatic vasculature in the human meninges. The data further suggest that Aß does not appear to widely deposit along wither these meningeal lymphatic or blood vessels, even among AD subjects.