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PROBING PRION CLEARANCE THROUGH INTERSTITIAL FLUID AND PERIVASCULAR PATHWAYS

Investigators
Sigurdson, Christina
Institutions
University of California - San Diego
Start date
2018
End date
2020
Objective
Prion diseases are neurodegenerative disorders characterized by rapid cognitive and motordecline. Similar to amyloid-? in Alzheimer?s disease, certain prion aggregates spread through thebrain and accumulate as parenchymal and vascular plaques. We hypothesize that prions, similarto amyloid-?, can transit through the interstitial fluid for clearance in perivascular channels. Werecently found that shortening heparan sulfate chain length in mice reduced parenchymal prionplaques yet increased vascular plaques in the brain, consistent with improved prion clearancethrough the interstitial fluid (ISF). Survival time was also prolonged. We and others also recentlyfound that the water transport protein, aquaporin 4, redistributes from astrocyte end feet in prion-affected blood vessels, indicating alterated perivascular channels in prion disease. In addition,aquaporin 4 expression is elevated in prion disease. In Aim 1, we will define when and howvascular channels and the blood brain barrier are modified during prion disease in humans andmice. In Aim 2, we will employ genetic mouse models with impaired CSF-ISF exchange todetermine how impairing fluid exchange impacts prion disease progression and phenotype. Wewill also establish the prion conformers that most severely modify water channel transportproteins, CSF-ISF fluid exchange, and the blood brain barrier in humans and in mice.
Funding Source
Nat'l. Inst. of Neurological Disorders and Stroke
Project source
View this project
Project number
1R21NS110409-01
Categories
Bacterial Pathogens
Viruses and Prions