Tuesday, April 29, 2025
4/29/2025
Targeting REV-ERB regulation of mitochondria as a therapeutic strategy in Alzheimer's disease - 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 mitochondria. 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, we hypothesize that REV-ERB is a critical regulator of bioenergetics, and therefore, pharmacological activation can be used to control mitochondrial function and protect against cellular energy deficits in AD. To this end, the research proposed here will aim to 1) elucidate molecular mechanisms employed by REV-ERB to modulate mitochondrial function and 2) determine the efficacy of pharmacological activation of REV-ERB as a therapeutic strategy targeting bioenergetic deficiencies in preclinical models of AD. We predict that 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.
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