PROJECT SUMMARY/ABSTRACT
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 (Aß) 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 Aß. 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 Aß
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 Aß 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 Aß 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.