The brain is comprised of multiple types of cells. They each have different roles and functions, but they also need to interact with each other to maintain a normal, healthy brain. Many CureAlz projects are examining the effects of Alzheimer’s disease on neurons and microglia alongside a rising tide of interest in astrocytes and immune cells. However, significantly less attention has been given to oligodendrocytes. Oligodendrocytes are a type of glial cell responsible for producing myelin, a lipid-rich substance that wraps around the axons of neurons. This myelin sheath acts as an insulator, enhancing the speed and efficiency of electrical signals that neurons use to communicate. Due to its high fat content, myelin appears pale and whitish, and large bundles of myelinated axons collectively form the brain’s white matter, whereas neurons make up gray matter. Although changes in white matter and myelin are observed in Alzheimer’s disease, very little is known about how Alzheimer’s disease pathologies impact oligodendrocytes or if changes in oligodendrocytes contribute to the onset or progression of the disease.
Dr. Gibson is investigating a novel hypothesis about the role of oligodendrocytes in Alzheimer’s based on two key observations: 1) Normal sleep patterns and circadian rhythms are disrupted in AD, and 2) Oligodendrocyte progenitor cells (OPCs), which make oligodendrocytes, proliferate on a circadian cycle, and this process is disrupted by sleep deprivation. Linking these together, Dr. Gibson and her team hypothesize that disruptions to the normal circadian clock in OPCs reduce myelination of neurons, leading in turn to changes in sleep that worsen Alzheimer’s-related pathologies. To enable investigation of the first part of this idea, Dr. Gibson’s lab developed a mouse model in which they deleted the well-known circadian clock gene Bmal1 in OPCs of embryonic mice. Once born, these mice had lower rates of OPC proliferation, less myelination around neurons, and fragmented sleep. As adults, these mice also developed cognitive deficits. Interestingly, deleting Bmal1 in adolescent or adult mice each produced different results than intervening in embryonic mice, suggesting that the timing of Bmal1-driven OPC dysfunction may determine its impact on Alzheimer’s disease.
The team proposed two aims to test their hypothesis linking OPCs and sleep with Alzheimer’s pathology. In the first aim, Dr. Gibson’s team is investigating the relationship between Bmal1 and amyloid pathology. To mimic the sleep disturbances and myelin deficits seen in AD, they are deleting Bmal1 in the OPCs of three different ages of amyloid mouse models (5xFAD). To assess how amyloid and myelin levels relate to OPC dysfunction, they are analyzing various sleep characteristics using techniques like EEG and EMG. In the second aim, they are differentiating human stem cells from control individuals, AD patients, or carriers of AD-related gene variants into OPCs in culture to investigate whether circadian-related genes are altered by disease in human OPCs. Finally, they are testing whether any of the identified genes influence OPC proliferation and myelin production in follow-up experiments using both human cells and mouse brains.
In the first year of funding, the team has made significant progress on their objectives. For Aim 1, they successfully generated amyloid mice (5XFAD) lacking Bmal1 in OPCs. When these mice—currently six weeks old—reach three and six months of age, they will be used in experiments to characterize changes in oligodendrocyte function, myelin structure, and sleep patterns. While waiting for the mice to reach the appropriate age, the team developed and optimized a new platform to isolate OPCs from their Bmal1 knockout mice and seed them onto brain slices from mice with a mutation in the myelin basic protein (MBP) gene, which impairs myelin production. This technique identified differences in oligodendrocyte morphology and myelin architecture, further supporting their preliminary findings of decreased myelin thickness in control mice that lack OPCs and Bmal1. Over the next year, they plan to continue these experiments to assess myelin and oligodendroglial architecture in OPCs derived from human Alzheimer’s stem cell lines. Additionally, they will conduct EEG recordings in their new mouse model and perform single-nucleus RNA sequencing to further investigate how the circadian system regulates OPC function and myelination in both mouse and human Alzheimer’s cell culture models.
