Can blocking a circadian clock protein fight Alzheimer’s?

A new study published in Nature Aging suggests that blocking a circadian clock protein called REV-ERBα may help reduce neurodegeneration in Alzheimer’s disease.
The researchers found that inhibiting REV-ERBα, either genetically or with a novel drug, led to increased levels of NAD+, a molecule used for cell functions such as DNA repair and metabolism.
Higher levels of NAD+ were associated with reduced tau pathology, the toxic aggregation of proteins in the brain that lead to neurodegenerative diseases.
The study’s findings provide evidence for a potential therapeutic approach to preventing and treating Alzheimer’s disease, particularly in reducing neurodegeneration.
The research was conducted by Erik Musiek and his team at Washington University in St. Louis, who genetically deleted REV-ERBα in mice models of Alzheimer’s disease and observed significant reductions in tau pathology and increased NAD+ levels.

A group of vintage alarm clocks on a table.

Impeding a link between the body’s natural clock and the brain may help reduce neurodegeneration in mice modeling Alzheimer’s disease, according to a new study

Erik Musiek, a professor of neurology at Washington University in St. Louis’ WashU Medicine, first author Jiyeon Lee, and colleagues conducted a study on mouse models of Alzheimer’s disease and found that inhibiting the function of a key protein in the circadian system can decrease levels of a harmful protein called tau and reduce neurodegeneration.

A circadian clock protein called REV-ERBα is known to control daily rhythms in metabolism and inflammation.

Though not well studied in the brain, REV-ERBα in other tissues has been shown to regulate nicotinamide adenine dinucleotide (NAD+), which is used for cell functions such as DNA repair and metabolism. Levels of NAD+ are directly correlated to brain aging and neurodegeneration—the lower the levels, the higher the amount of brain aging.

In fact, many supplements currently available on the market claim to increase NAD+ levels to decrease aging.

Musiek and his team genetically deleted REV-ERBα throughout all tissues in one group of mice, and, in a separate group of mice, they deleted the protein only in astrocytes—glial cells that make up much of the central nervous system. NAD+ levels increased in both instances.

This provided evidence that REV-ERBα deletion in astrocytes has a direct impact on the levels of NAD+ in the brain, providing a pathway for potential neurodegenerative treatment studies in the future.

The researchers also discovered that inhibiting REV-ERBα, both genetically and with a novel drug that has shown promise in amyloid-β pathology and Parkinson disease studies, led to higher levels of NAD+ and protected the mice from tau pathology, the toxic aggregation of proteins in the brain that lead to neurodegenerative diseases.

The results from the experimental drug may reveal a new therapeutic approach to preventing and treating Alzheimer’s disease.

The study appears in Nature Aging.

Source: Washington University in St. Louis

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Q. What is the circadian clock protein REV-ERBα?

A. REV-ERBα is a protein that controls daily rhythms in metabolism and inflammation, and has been shown to regulate nicotinamide adenine dinucleotide (NAD+) levels.

Q. How does REV-ERBα relate to NAD+ levels in the brain?

A. Lower levels of NAD+ are directly correlated to brain aging and neurodegeneration, while higher levels may have protective effects against these conditions.

Q. What is the role of astrocytes in the central nervous system?

A. Astrocytes are glial cells that make up much of the central nervous system, and REV-ERBα deletion in astrocytes has been shown to impact NAD+ levels in the brain.

Q. Can blocking a circadian clock protein like REV-ERBα help fight Alzheimer’s disease?

A. Yes, inhibiting the function of REV-ERBα has been shown to decrease levels of the harmful protein tau and reduce neurodegeneration in mice modeling Alzheimer’s disease.

Q. What is amyloid-β pathology, and how does it relate to Alzheimer’s disease?

A. Amyloid-β pathology refers to the toxic aggregation of proteins in the brain that lead to neurodegenerative diseases like Alzheimer’s.

Q. How did the researchers study the effects of REV-ERBα deletion on NAD+ levels and tau pathology?

A. The researchers genetically deleted REV-ERBα throughout all tissues in one group of mice, and in a separate group, they deleted the protein only in astrocytes.

Q. What is the potential therapeutic approach revealed by this study?

A. The results suggest that inhibiting REV-ERBα may provide a new therapeutic approach to preventing and treating Alzheimer’s disease.

Q. How did the researchers’ findings relate to existing supplements on the market?

A. Many supplements claim to increase NAD+ levels to decrease aging, which is consistent with the study’s finding that inhibiting REV-ERBα increases NAD+ levels in the brain.

Q. What is the significance of this study for future neurodegenerative treatment studies?

A. The study provides evidence that REV-ERBα deletion in astrocytes has a direct impact on NAD+ levels in the brain, providing a potential pathway for future neurodegenerative treatment studies.