Disturbances of the sleep-wake cycle and circadian rhythms, the 24-hour oscillations which govern many aspects of bodily function, are associated with aging and are common in many neurodegenerative diseases, including Alzheimer’s Disease (AD). Emerging evidence strongly suggests that disrupted sleep and circadian rhythms can lead to increased accumulation of amyloid-beta (Aβ), a peptide key to the pathogenesis of AD. Aβ levels in the brain also show a clear day-night rhythm which is tied to the sleep/wake cycle. Circadian and sleep rhythms are generated by the master clock of the body, the suprachiasmatic nucleus (SCN) of the hypothalamus. SCN function declines with age in mice and humans, leading to disrupted rhythms. While age- and disease-related declines in sleep and circadian function have been hypothesized to contribute to neurodegeneration, no methods to specifically manipulate these circadian rhythms have been available. We propose to use optogenetics, a method of stimulating neuronal activity in the brain using light, to stimulate or suppress neurons in the SCN of mouse models of AD. We will determine if acutely altering the firing of the SCN, and thus the circadian rhythms of the animal, can change the dynamics of Aβ levels in the brain. We will also determine if properly-timed optogenetic activation of SCN can rejuvenate the impaired circadian rhythms in mouse models of AD. We hope to create a novel method of “fixing the broken clock” which can be applied across neurodegenerative disease models, in order to understand how circadian function impacts neurodegeneration.
Grants and Awards
“Circadian Regulation of MemoryDuring Alzheimer’s Disease Pathogenesis”
NIH/NIA 5R01AG063834 (PI, Kress)
Public Health Relevance Statement, Project Narrative: Cognitive decline is the defining feature of Alzheimer’s disease. There are no effective treatments to slow the progression of Alzheimer’s disease. This project has the potential to identify new treatments by studying the relationship between the circadian system and cognitive function during Alzheimer’s disease progression.
“Resetting the Clock in Alzheimer’s Disease”
2017 McDonnell Center for Systems Neuroscience, Washington University in St. Louis (PI, Kress)