SCD inhibition reverses immune, synaptic and behavioral deficits in an animal model of Alzheimer's disease [scRNA-Seq]

Early- and late-onset forms of Alzheimer's disease (AD) share common features that include abnormalities in lipid metabolism, immune response and synaptic function. Of these, the role of lipids remains the least understood. Our study revealed that molecular functions related to Stearoyl-CoA Desaturase (SCD), the rate limiting enzyme in monounsaturated fatty acid synthesis were specifically altered in the hippocampus of 3xTg-AD (a model of early-onset AD). Remarkably, infusion of an SCD inhibitor (SCDi) reversed 40% of altered immune and synapse genes, rescue dendritic spine number and structure, recovered activity-associated immediate-early gene expression and restored learning and memory in 3xTg-AD mice. In addition, we employed single cell RNA sequencing to characterize the cellular landscape of microglia subpopulations within the 3xTg hippocampus and uncovered that SCDi reversed microglial activation and polarization. Together, we show that a single lipid enzyme, SCD, impinges on the core features of AD. Overall design: For each treatment group the ipsilateral hippocampi from 4 animals were dissociated into single cells and pooled before staining with CD45 mutiplexing kit from BD Biosciences.