Unique transcriptomic alterations in 5XFAD;PS19 mouse model align with human Alzheimer's disease

To investigate this, we generated a dual-pathology mouse model (5XFAD;PS19) and performed single-nucleus RNA sequencing (snRNA-seq), integrating findings with human AD datasets. We uncovered widespread, synergistic transcriptional disruptions not seen in single-pathology models, including changes in gene co-expression networks and cell type-specific gene expression.

Notably, we observed coordinated transcriptomic alterations involving both microglia and oligodendrocytes, particularly in immune-related pathways and suppression of synaptic transmission. The combined model significantly overlapped with human AD transcriptomic profiles at both gene and pathway levels, highlighting its translational relevance. This well-powered, sex-balanced study dissects the synergistic effects of Aβ and tau across multiple brain cell types.