The brain contains multiple cell types, including neurons, astrocytes, microglia, oligodendrocytes, vascular cells, and infiltrating immune cells from the periphery. While much of the field focuses on how Alzheimer’s disease (AD) impacts neurons and microglia—and increasingly astrocytes and peripheral immune cells—there has been much less attention paid to the oligodendrocyte. Oligodendrocytes are a type of glial cell that forms a lipid-rich substance called myelin. Myelin wraps like a sheath around the long axon processes of some neurons, where it helps transmit the electrical signals that carry information from one neuron to another. Bundles of myelinated axons form the white matter of the brain, so named because myelin is light in color. White matter is lost in AD and may directly contribute to clinical symptoms, since memory formation and recall depend in part on healthy myelin. Results of several new studies suggest that oligodendrocyte and myelin disruption may occur early in the disease, before amyloid levels rise in the brain. Further research into the causes and mechanisms of oligodendrocyte dysfunction may illuminate novel therapeutic targets for AD.
Dr. Gaultier’s preliminary research into these mechanisms points to the cGAS-STING pathway, which triggers an inflammatory response when DNA is damaged or detected where it should not be (i.e., outside the nucleus). This activation is typically protective, as it recognizes and eliminates DNA-containing pathogens; however, like other immune responses, it may be detrimental if left unchecked. Because oligodendrocytes are more susceptible to DNA damage than other cell types, the cGAS-STING pathway might have a particularly important protective role. However, this same vulnerability could leave them especially susceptible to damage if the immune response gets out of hand.
Dr. Gaultier’s team recently found that a substantial loss of myelin occurs in the 5XFAD amyloid mouse model. Because oligodendrocytes in these mice and in Alzheimer’s patients exhibit increased DNA damage—and given that damaged DNA has been shown to activate the cGAS-STING signaling pathway in other cell types in the context of AD—the team hypothesized that DNA damage in oligodendrocytes may contribute to myelin loss through the cGAS-STING signaling axis.
Dr. Gaultier is testing this hypothesis via two experimental aims. In the first aim, they are assessing the impact of DNA damage and STING signaling on oligodendrocyte function in cultured cells. They are generating DNA damage in mouse oligodendrocytes using several approaches that model the variety of ways that DNA can be damaged, e.g., chemicals that create breaks in DNA, mimic effects of environmental pollutants, cause oxidative stress, or cause specific mitochondrial DNA damage. They are also adding toxic forms of amyloid alone and in combination with DNA-damaging treatments. Further, they are performing these experiments in genetically engineered mouse cells that lack STING. They predict that cells without STING will be protected from the effects of DNA-damaging agents on myelin. They are measuring several outcomes after these manipulations: cell death, myelin, cGAS-STING activation, inflammation, and metabolic functions. In the second aim, they are investigating how STING signaling impacts myelin and cognition in a newer generation amyloid mouse model (APP-NLGF). These mice better mimic the typical expression of the amyloid precursor protein in all brain cell types, including oligodendrocytes, compared to the 5xFAD model, which is biased toward neurons. They have bred APP-NLGF mice with the mice described above that completely lack STING in oligodendrocytes. They are then characterizing brain changes in these mice across multiple ages to determine how oligodendrocyte cGAS-STING signaling contributes to the progression of amyloid-related pathologies in APP-NLGF mice. They are specifically measuring oligodendrocyte numbers and function, as well as axon damage and myelin integrity. They are also performing behavioral tests to investigate the impact of blocking STING on learning and memory functions.
Dr. Gaultier’s team made significant progress across both aims of the project during the first year of funding. While much of the work focused on the second aim, several experiments related to the first aim demonstrated that direct activation of STING alters oligodendrocyte function and the expression of myelin basic protein, a key component of myelin. The team successfully generated the mouse lines outlined in the second aim and conducted several key experiments with them. Specifically, they found that selective deletion of STING in oligodendrocytes modifies disease progression. In the second year, the team plans to complete the remaining experiments for the first aim and replicate the second-aim experiments in APP-NLGF mice to determine whether the trends observed in the more aggressive 5XFAD model are conserved in this less severe amyloid model.
