Dr. Nedergaard’s project builds on her lab’s pioneering work on the brain’s glymphatic system, through which cerebrospinal (CSF) circulates through the brain, accumulating waste products before draining out of the brain. Astrocytes are critical components of this transport system because they form tunnels around blood vessels through which CSF fluid flows. Previous research shows that lowering the levels of an astrocyte gene called AQP4 dramatically slows down amyloid beta clearance.
The Nedergaard lab has continued to investigate many aspects of the glymphatic system—from entry to exit points—and as part of these studies, they recently reported another remarkable finding: the discovery of a brain-meninges barrier that they termed the Subarachnoid Lymphatic-like Membrane (SLYM). The classic textbook description of the meninges surrounding the brain states that it comprises three layers: the dura, arachnoid, and pia membranes. Remarkably, Dr. Nedergaard’s team reported evidence of a fourth layer in both mice and humans. They further demonstrated that the SLYM acts as a barrier to restrict the exit of certain-sized molecules and directs the clearance of different waste products via the CSF (exit, not entry). Dr. Nedergaard hypothesizes that the SLYM is a key exit point for glymphatic fluid and that degeneration of the SLYM compromises the clearance of amyloid beta in Alzheimer’s disease.
The team proposed three aims using gene expression analyses and advanced imaging methods in an amyloid mouse model (APP/PS1). In the first aim, they are characterizing the cellular and molecular changes occurring in SLYM cells during disease progression in amyloid mice compared to controls to determine how these relate to several pathology measures. In the second aim, they are mapping the functional changes of the SLYM barrier with aging and disease progression in amyloid mice compared to controls. In the third aim, they are investigating the role of SLYM in directing the export path of proteins made by brain cells.
Over the course of the first year, the team established key tools for studying SLYM function in Alzheimer’s disease, including a single-cell characterization protocol and two imaging techniques to assess SLYM permeability and protein clearance. Initial findings suggest that in amyloid mice, dysfunction of the SLYM impedes waste outflow in APP/PS1 mice. In the upcoming year, the Nedergaard team will refine their gene expression analyses, further optimize their imaging methods, and investigate how SLYM dysfunction affects clearance pathways, including routes to cervical lymph nodes.
