Disturbances in sleep and other daily (circadian) rhythms are common in people living with Alzheimer’s disease. Evidence suggests that these disturbances can both contribute to Alzheimer’s pathology and can result from it, but the exact relationships among the various aspects of sleep and circadian rhythm and Alzheimer’s pathology are not yet elucidated. Sleep, the most well-known circadian rhythm, is closely tied to the two key proteins involved in Alzheimer’s: amyloid and tau. Levels of these proteins increase while we are awake, but their clearance from the brain increases while we sleep. When sleep is disrupted, their levels remain elevated, which can lead to their accumulation in the brain. As a result, researchers are exploring whether improving sleep and restoring healthy circadian rhythms could prevent or slow the progression of Alzheimer’s disease.
Circadian clock dysfunction can occur in two significant ways: either by losing amplitude (arrhythmicity, or the amount of difference between one stage and another) or by falling out of sync with external cues, such as daylight (desynchrony). Dr. Musiek’s team previously investigated how arrhythmicity impacts Alzheimer’s and Parkinson’s-related pathologies by deleting a key circadian clock gene in mice called BMAL1. In amyloid-expressing mice, BMAL1 removal caused more amyloid plaques to build up in the brain, supporting the idea that disrupted circadian rhythms contributed to Alzheimer’s pathologies. However, in mouse models of tau and alpha-synuclein (the hallmark protein of Parkinson’s), BMAL1 deletion unexpectedly caused levels of these proteins to decrease. It was unclear whether these findings stemmed from the loss of circadian function itself or were a byproduct of the experimental method to remove BMAL1.
To explore these unexpected results further, Dr. Musiek turned to the other form of clock dysfunction: desynchrony. Unlike arrhythmicity, which involves a loss of internal rhythm, desynchrony occurs when the internal clock becomes misaligned due to environmental cues—something many people experience as a result of nighttime light exposure, digital screens, shift work, or travel across time zones. The Musiek team argues that studying desynchrony may have significant translational relevance for patients, given how common these stressors are. To trigger desynchrony in mice, they simulate jet lag by shifting the light-dark cycle six hours earlier each week, mimicking traveling east across six time zones, for three months. Preliminary data showed that this “jet lag” increased amyloid buildup and decreased alpha-synuclein pathology, similar to what they found in their arrhythmia studies. Both types of circadian disruptions also activated astrocytes in the brain, a type of glial cell that plays multiple roles in supporting brain health. Based on these results, the Musiek team hypothesizes that circadian desynchrony alters astrocyte behavior in a way that increases amyloid plaque pathology while suppressing other pathologies like alpha-synuclein accumulation.
In the current proposal, they are testing this hypothesis across two aims. The first investigates whether astrocytes mediate the effects of jet lag on amyloid and alpha-synuclein pathologies. Using RNA sequencing, the team is characterizing astrocyte activation in amyloid, alpha-synuclein, and control mice exposed to jet lag. They will then block astrocyte activation in each to determine if this prevents the increase in amyloid plaque burden or the decrease in alpha-synuclein pathology. The second aim will use amyloid mouse models to test two potential interventions to reduce the impact of jet lag on amyloid pathology. The first of these experiments tests a counterintuitive idea: that weakening the internal circadian clock might protect against jet lag by making it less responsive to external cues and thus less susceptible to becoming desynchronized. To test this, the team is exposing mice with an impaired circadian clock to jet lag conditions and measuring the effect on amyloid buildup. The second intervention uses timed feeding as a stabilizing circadian cue. Since food, like light, helps set circadian rhythms, the Musiek lab is restricting food to the dark phase (when mice are normally active) of the jet lag protocol to see if this reduces amyloid accumulation. Both strategies explore whether different forms of circadian training can reduce the harmful effects of desynchrony.
During the first funding period, Dr. Musiek’s team made significant progress toward completing their proposed experiments. They discovered that the gene expression changes in astrocytes following chronic jet lag do not appear immediately but instead emerge two weeks after the jet lag protocol ends. As a result, the team is now focusing their analyses on this delayed time point. They also identified several key stress-related signaling pathways affected by jet lag, including the JAK2/STAT3 pathway. This critical and far-reaching signaling axis impacts a litany of cell functions. Dr. Musiek’s team plans to probe the impacts of this pathway in future experiments. Other disrupted pathways, found in both wild-type and amyloid (APP/PS1) mice, involve metabolic and inflammatory signaling. In pursuit of the second aim, Dr. Musiek encountered issues with the initially proposed mouse model for impaired circadian function. This led to the development of a new model, which caused some delays, but Dr. Musiek expects to complete the experiments in the second funding period. Meanwhile, the time-restricted feeding experiments designed to prevent circadian desynchrony are underway. Dr. Musiek has expanded this aim to include the APOE4:P301S tauopathy mouse model, as the impact of time-restricted feeding on tauopathy has never been tested. These additional experiments are also expected to be completed in the second funding period.
