Genomic stress and STING activation in oligodendroytes drives Alzheimer's Disease
Oligodendrocytes are a vital yet understudied cell type, especially in the case of neurodegeneration. This is despite their potential to mitigate neuronal degeneration through axonal structural support and metabolic supplementation, which may be pivotal in reinforcing neurons in times of cellular stress. Neuronal degeneration runs rampant in Alzheimer's Disease (AD), which is the most common form of dementia. Exhaustive research into AD pathogenesis has yet to yield safe and effective treatment. Even the most recent amyloid monoclonals do little to slow progression of disease and indeed any improvement seems to be clinically indiscernible. Additionally, these drugs carry a significant risk of vascular events. While amyloid-beta and tau accumulation and neuronal pathology are main hallmarks of AD, a wide cascade of cellular events are also present. Demyelination is a prominent pathological hallmark of AD and has even been shown to occur in the preclinical phase of disease. Studies have suggested that oligodendrocyte and myelin deficits precede tau and Aß accumulation, perhaps playing their own role in precipitating neurodegeneration and neuronal/axonal decline. The mechanisms of oligodendrocyte dysfunction in AD remain unknown. DNA damage has been increasingly linked to AD progression, and markers of DNA damage have been shown to be upregulated in oligodendrocytes in particular within both AD patients and animal models. This DNA damage can activate the nucleic-acid sensing pathway mediated by stimulator of interferon related genes (STING) as well as the Type I interferon response, further impacting oligodendrocyte homeostasis. DNA damage in oligodendrocytes and its ramifications could deprive neurons of crucial support, thereby accelerating degeneration. Indeed, DNA damage in oligodendrocytes as well as the role its resulting cascade of pathways have in the AD brain have not yet been explored. Overall design: spatial transcriptomic profiling of Olig2+ cells in AD patient tissue (from normal aging, prelinical disease, and AD as identified by Braak score) costained with beta-amyloid. White matter, grey matter regions as well as regions with plaque and devoid of plaque were identified and sequenced using the GeoMx platform.