Sleep-wake disruptions and cognitive impairments are prevalent and disabling features of Alzheimer's disease (AD). AD patients exhibit profound sleep disturbances including disruption of non-rapid eye movement (NREM) sleep. A major restorative feature of NREM sleep, which is also associated with proper cognitive functioning, is slow-wave activity (SWA). Recent findings suggest a causal relationship between impaired generation of SWA during sleep and AD pathogenesis including extracellular accumulation of the amyloid-? (A?) peptide and neuronal dysfunction. While evidence indicates that cortical-thalamic loops regulate SWA, the exact cellular and molecular mechanisms for impaired SWA in AD are unknown. Thus, a need exists to characterize the cells and molecular mechanisms responsible for SWA generation to reduce the impairments in SWA and pathogenesis of AD. We propose studies that will elucidate the sleep state related mechanisms by which SWA protects against AD. Studies using AD animal models suggest that inhibitory neurotransmission is impaired during periods of SWA. The overall objective of this proposal is to identify and stimulate specific SWA modulating interneuronals to determine which cells restore SWA and mitigate AD-related pathology using an established AD mouse model. Herein, we propose to employ optogenetics and chemogenetics to control neuronal circuits aimed to restore SWA and slow AD progression. Thus, our findings will determine the cellular and molecular relationships between sleep and AD, with the targeting of interneurons during specific periods of sleep as a novel therapeutic approach.

Public Health Relevance

We propose to determine the cellular and molecular relationships between sleep and Alzheimer's disease, with the targeting of interneurons during specific periods of sleep as a novel therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG061774-01
Application #
9672140
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2019-04-15
Project End
2024-03-31
Budget Start
2019-04-15
Budget End
2024-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115