PROJECT SUMMARY
Alzheimer's disease (AD) is a devastating neurologic disorder that affects millions of people worldwide. In
the United States, over 5 million people are currently living with AD, and it is the 6th leading cause of
death. Despite decades of intensive research, effective treatment strategies are lacking, and with the
incidence expected to rise in the coming decades, there is a significant unmet need for novel AD
therapeutics. The hallmarks of AD include extracellular amyloid plaque deposition, intracellular tau
hyperphosphorylation leading to neurofibrillary tangle formation, neuroinflammation, and ultimately,
neuron cell loss. Although the mechanisms driving these hallmarks are not entirely clear, it is
generally accepted that each of these pathophysiological hallmarks is deleterious, and together, they
precipitate devastating cognitive and psychiatric impairments. In addition to the pathological hallmarks of AD,
some basic pathophysiological disturbances are also present. Mitochondrial function, which is critical for cell
health, is one of these physiological processes commonly perturbed in patients with AD and animal
models of the disease. Under normal physiological circumstances, mitochondria are essential for energy
metabolism, however in diseased states, mitochondria become inefficient, oxidative stress increases, and
cellular damage is inevitable. In AD, mitochondria are highly dysregulated and become increasingly
dysfunctional. Interestingly, circadian rhythm, which is also perturbed in patients with AD, greatly influences
mitochondrial function. Indeed, the nuclear receptor REV-ERB, which is a critical transcriptional regulator of
circadian rhythm, has been shown to control mitochondrial function and energy metabolism. Thus, I
hypothesize that REV-ERB is an important regulator of bioenergetics, and therefore, pharmacological
activation can be used to control mitochondrial function and protect against cellular energy deficits in AD.
Furthermore, this preservation of energy dynamics in AD could prevent or improve cognitive and
psychiatric impairments in the disease. To this end, the research proposed here will aim to 1) elucidate the
mechanism(s) governing REV-ERB regulation over bioenergetics and 2) investigate the efficacy of
pharmacological activation of REV-ERB to mitigate bioenergetics deficiencies and ensuing cognitive
impairment in a preclinical genetic model of AD. These studies will advance our understanding of REV-ERB
function in the brain and provide the basis for a novel therapeutic strategy in the treatment for Alzheimer's
disease.