There is currently no cure for Alzheimer?s disease, the most prevalent cause of dementia worldwide, and the limited treatments only slow disease progression. Alzheimer?s disease is characterized by pathogenic amyloid beta (A?) plaque accumulation, tau tangles, and cognitive impairment. Subclinical epileptiform activity or seizures, which are indicative of network hyperexcitability, are also present in early Alzheimer?s disease (defined by normal cognition and preclinical plaque pathology). Interestingly, epileptiform activity is greater and seizure thresholds are lower during the inactive phase (night in humans) in general and in Alzheimer?s disease. This may be exacerbated in Alzheimer?s disease patients because of documented disruptions in their sleep wake cycle, which is driven by the circadian clock. Circadian rhythms are endogenous oscillations in physiology and behavior occurring over a 24-hour period. They are driven by a cellular transcription-translation feedback loop, involving the proteins BMAL1, PER1/2, and CRY1/2, collectively known as the molecular clock. Circadian rhythm driven day-night differences are seen in healthy cognitive function, network activity (epileptiform activity and seizures), and protein expression, including proteins involved in synaptic function and pathogenic proteins such as A?. While these rhythms are perturbed in Alzheimer?s disease, little work has been done to investigate the consequences of day-night disruptions of neurophysiology in Alzheimer?s disease and how these disruptions might exacerbate disease pathology. Published literature and preliminary data suggest that decreased inhibition during the day plays a role in the observed hyperexcitability and cognitive impairment, but little has been done to elucidate the role of loss of day-night differences in hippocampal inhibition in cognitive impairment and A? pathology. This proposal aims to test the hypothesis that the loss of hippocampal day-time inhibition in Alzheimer?s disease contributes to cognitive impairment and A? pathogenesis by determining if this day-night difference in physiology is altered in the J20 mouse model of Alzheimer?s disease, and if restoring this day-night difference is necessary and sufficient to rescue cognitive impairment and A? pathology. This will be accomplished through electrophysiology, chemogenetics, biochemical, and behavioral assays. Additionally, the proposed experiments will be completed under the guidance of my sponsor and co-sponsor, both experts in circadian clocks and Alzheimer?s disease respectively, as well as in an environment ideally suited for understanding the molecular and functional deficits contributing to Alzheimer?s disease. Uncovering day-night differences in physiology and disruptions of that physiology will not only provide insight to possible therapeutic targets, but also when interventions should be administered to most effectively ameliorate Alzheimer?s disease symptoms or delay pathological onset.
Alzheimer?s disease is the most prevalent cause of dementia worldwide affecting over 5 million people in the United States alone with treatments that only manage symptoms and no cure. We propose to examine how day- night differences in neurophysiology affect cognition and amyloid beta pathology in Alzheimer?s disease through electrophysiological, biochemical, chemogenetic, and behavioral assays. Given that Alzheimer?s disease patients exhibit circadian dysregulation in cognitive function and amyloid beta expression, understanding circadian timing of neurophysiology is critical to understanding and treating Alzheimer?s disease.
