Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease -- Early-stage AD

Alzheimer's disease (AD) exhibits imbalance between neuronal excitation and inhibition, likely secondary to interneuron dysfunction. To reveal underlying mediators, we profiled the transcriptome of neuronal subtypes in 5XFAD versus control mice at early- and late-stage disease. Pooled analysis of neuron types showed expected pathways at early-stage (RNA and protein processing pathways) versus late-stage (neurodegenerative pathways) disease. Early-stage interneurons exhibited alterations in AD-related RNA and protein pathways along with canonical neurodegenerative pathways. Early-stage excitatory neurons, however, showed changes in axon guidance and synapse pathways, without representation of neurodegenerative pathways. Classical neurodegenerative pathways were represented only in late-stage excitatory neurons. Late-stage interneurons instead featured neuronal and synapse pathways along with cellular, cancer, and infection pathways. Our results suggest earlier neurodegenerative pathway involvement in interneurons, represented in excitatory neurons only at later stages, possibly indicating earlier inhibitory neuron involvement. These transcriptomic profiles offer insight into potential AD pathophysiology and therapeutic targets. Overall design: Spatial transcriptomics was performed by GeoMx DSP (NanoString, Seattle, WA), a platform for spatially analyzing gene expression in tissue in a highly multiplexed manner.64 Four slides in total were submitted for spatial transcriptomics. Two slides were for early-stage analysis and were duplicates of 4 brain sections (n=2 5XFAD 12 wk, n=2 controls 12 wk)