Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse

Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.