Brain Entry and Exit Consortium: Central Nervous System Fluid Homeostasis and Waste Clearance in Alzheimer’s Disease Characterized by MRI

2022

Alzheimer’s disease (AD) is the most common neurodegenerative disorder of older adults and is characterized by slowly progressive and irreversible dementia. This fatal and currently incurable disease affects millions of people worldwide, including 1 in 10 adults older than 65. AD is associated with the progressive accumulation of two key waste proteins: misfolded amyloid-beta (Aβ) and hyperphosphorylated tau. Recent studies have shown that therapeutically targeting early-onset amyloid-beta deposition might be key in preventing progressive cognitive decline and dementia later in life. The glymphatic and lymphatic systems are capable of removing brain waste products, including amyloid-beta and tau, and therefore hold strong promise of constituting alternative therapeutic targets for the prevention of AD. Over the last decade, much new knowledge has been gained on the functioning of the glymphatic and lymphatic systems in the live brain. However, some important parameters that are key to understanding glymphatic-lymphatic system function remain poorly understood; one is brain waste clearance rates (i.e., how a given “waste particle” moves inside the brain) in relation to local water mobility across the central nervous system (CNS). This information is critical in order to understand how fluid flow within the glymphatic-lymphatic systems might be therapeutically adjusted to sustain or accelerate brain waste disposal. Our project is focused on addressing the aforementioned critical gaps in knowledge: 1) determining waste clearance from the brain and its relation to water mobility as well as to lymphatic drainage in rats with and without AD, and 2) determining the relation between abnormal fluid flows observed in AD rats and cerebrospinal fluid secretion from the choroid plexus. Successful performance of our proposed experiments will advance therapeutic strategies for AD.


Funding to Date

$286,404

Focus

Studies of Alternative Neurodegenerative Pathways, Translational

Researchers

Helene Benveniste, M.D., Ph.D.


Allen Tannenbaum, Ph.D.