Tauopathies are a class of neurodegenerative disorders characterized by abnormal aggregation of the tau protein that affect over 5 million people in the United States and include diseases such as Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), and some forms of Frontotemporal Dementia (FTD). Tauopathy is also a prominent feature of Alzheimer's disease. In addition to neurodegeneration, tauopathies are associated with increased sleep disturbances including insomnia, excessive daytime sleepiness, and rapid eye movement (REM) sleep behavior disorder. Up to 76% of FTD patients exhibit sleep disturbances of some kind and a high percentage of CBD and PSP patients suffer from insomnia. These sleep disorders are a major cause of institutionalization. Sleep is an important biological function that facilitates learning and memory as well as metabolic homeostasis of proteins within the brain. Despite the importance of sleep and the high prevalence of sleep disturbances in tauopathies, little is known about the role of tau pathology in sleep disruption. The objective of this work is to study the interaction between sleep disturbances and tau pathology, which could ultimately lead to better treatments for tauopathy-related sleep disorders, improvements in care, and decreases in institutionalization, as well as possibly providing a strategy for slowing disease progression itself. Preliminary analysis of sleep/wake behavior in aged tauopathy mouse models of FTD with Parkinsonism-17 (P301S) demonstrates that tau pathology significantly decreases delta power during non-rapid eye movement sleep (NREM) sleep and theta power during REM sleep compared to wild-type controls. Aged P301S human tau mice also show a trend towards increased time in wake and decreased time in sleep. We hypothesize that sleep disturbances increase with tau pathology progression and that sleep deprivation results in increased tau pathology in the brain. This proposal uses in vivo quantitative electroencephalography with electromyography to analyze the effect of tau pathology progression on sleep/wake behavior as well as anti-tau antibody treatment to determine if insoluble tau is causative of sleep deficits. Additionally, this project ill investigate the effects of chronic and short-term sleep deprivation on tau pathology as well as tau levels in the brain interstitial fluid to determine if decreased sleep, as seen in tauopathy patients, affects disease progression.

Public Health Relevance

Tauopathies are a class of neurodegenerative disorders that affect over 5.4 million people in the United States. Additionally, tauopathy patients have a high prevalence of sleep disturbances including insomnia, excessive daytime sleepiness, and rapid eye movement sleep behavior disorder which are a major cause of institutionalization. Tauopathies are characterized by abnormal aggregation of the tau protein and understanding the interaction between sleep disturbances and tau pathology could lead to better treatments for tauopathy-related sleep disorders, improvements in care, and decreases in institutionalization, as well as possibly providing a stragegy for slowing disease progression itself.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS089381-01
Application #
8782732
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130