New research in mice has uncovered a significant link between a protein integral to the body’s daily rhythms and the processes of brain aging and neurodegeneration. Scientists at Washington University School of Medicine in St. Louis found that by impeding the function of this circadian clock protein, they could protect against the kind of brain damage seen in Alzheimer’s disease. The findings, published in Nature Aging, open a new avenue for developing therapies aimed at neurodegenerative conditions.
The study focused on a protein named REV-ERBα, which plays a key role in managing the body’s internal 24-hour clock. The researchers discovered that inhibiting this protein led to an increase in a vital cellular molecule, nicotinamide adenine dinucleotide (NAD+), which is known to decrease with age. This boost in NAD+ levels, in turn, helped protect the mouse models from the accumulation of harmful tau protein, a hallmark of Alzheimer’s and other neurodegenerative diseases, ultimately reducing brain cell death and damage.
Mechanism of Neuroprotection
The core of the study’s findings lies in the relationship between the circadian protein REV-ERBα and the cellular fuel source NAD+. In various tissues, REV-ERBα is known to regulate metabolism and inflammation, but its function within the brain was less understood. The research team established a direct correlation between REV-ERBα activity and NAD+ levels in the brain.
NAD+ is crucial for numerous cellular functions, including DNA repair and maintaining a healthy metabolism. Its levels are known to decline significantly during the aging process, and this decline is closely linked to age-related diseases and neurodegeneration. Many commercially available supplements aim to boost NAD+ to counter aging effects. This study demonstrated that by targeting REV-ERBα, it is possible to naturally increase NAD+ levels within the brain itself, offering a more targeted approach to tackling the deficiencies associated with brain aging.
The Role of Astrocytes
A key part of the investigation involved identifying which cells in the brain were central to this protective mechanism. The researchers focused on astrocytes, a type of glial cell that makes up a significant portion of the central nervous system and provides critical support to neurons.
Targeted Gene Deletion
To pinpoint the source of the NAD+ increase, the team conducted experiments using genetically modified mice. In one group, they deleted the gene for REV-ERBα in all tissues throughout the body. In a second group, the deletion was confined only to the astrocytes. In both scenarios, the levels of NAD+ in the brain increased significantly. This powerful result provided the first direct evidence that REV-ERBα within astrocytes has a substantial impact on the overall availability of NAD+ in the brain. By showing that manipulating astrocytes alone was sufficient to raise NAD+, the study highlights these cells as a promising target for future therapies.
Therapeutic Approaches and Results
The researchers tested two distinct methods for inhibiting REV-ERBα to see if they could achieve neuroprotective effects in mouse models of Alzheimer’s disease, which are engineered to develop tau pathology.
Genetic and Pharmaceutical Inhibition
The first approach was genetic, using the mice with the REV-ERBα gene deleted. The second approach involved administering a novel drug designed to block the protein’s function. This experimental drug had previously shown potential in studies related to amyloid-beta pathology, another hallmark of Alzheimer’s, as well as in models of Parkinson’s disease.
Both methods yielded positive results. The inhibition of REV-ERBα, whether through genetic modification or the experimental drug, led to higher NAD+ levels and successfully protected the mice from the toxic aggregation of tau proteins in their brains. This intervention shielded the neurons from damage and reduced the overall neurodegeneration that typically occurs in these disease models.
Implications for Future Treatments
The findings from this study suggest a new therapeutic strategy for preventing and treating Alzheimer’s disease and potentially other neurodegenerative disorders. By focusing on the circadian system, specifically the REV-ERBα protein, researchers may be able to counteract the age-related decline in NAD+ and fortify the brain against pathological damage. The success of the experimental drug in mice is particularly promising, as it points toward a viable pharmacological approach for human patients.
Disruptions to circadian rhythms, such as altered sleep patterns, are a common symptom in patients with Alzheimer’s, Parkinson’s, and Huntington’s disease. For a long time, it was unclear if this was a cause or a consequence of the underlying neurodegeneration. This research, along with other studies in the field, substantiates the idea that a malfunctioning internal clock can be a contributing factor to the onset and progression of these diseases. Therefore, therapies aimed at restoring or manipulating components of the circadian clock may offer a powerful way to promote brain health during aging.