Alzheimer’s disease is characterized by decades-long accumulation of amyloid beta prior to cognitive decline, yet therapeutic strategies targeting amyloid after plaque formation have yielded limited clinical benefit. As such, identifying fundamental upstream drivers and mechanisms is an important objective for developing new therapies for AD.
Dr. Nedergaard believes that one such upstream driver of amyloid aggregation is dysfunction of the brain’s waste-clearance system. In the healthy brain, CSF transport operates as a highly organized, directional system with CSF production and drainage separated and distinct. The breakdown of this organized system, Dr. Nedergaard posits, is a targetable upstream driver of AD. Dr. Nedergaard and her team previously identified the subarachnoid lymphatic-like membrane (SLYM) as a structural organizer that maintains the separation and directionality of this system.
This project will define when and where the separation and directionality of the CSF flow fail across multiple AD mouse models and determine whether this dysfunction leads to amyloid plaque deposition. They will use transcriptome data to identify therapeutic target with the aim of prolonging SLYM integrity. These studies establish a mechanistic framework for AD as a disorder of CSF clearance failure and identify SLYM as a therapeutically actionable target.
