Abstract
The lack of natural aging-inducing Alzheimer's disease (AD) model presents a significant gap in the current preclinical research. Here, we identified a unique cohort of 10 naturally aging tree shrews (TSs) displaying distinct Alzheimer's-like pathology (ALP) from a population of 324, thereby establishing a novel model that closely mirrors human AD progression. Using single-nucleus RNA sequencing, we generated a comprehensive transcriptome atlas, revealing the cellular diversity and gene expression changes underlying AD pathology in aged TSs. Particularly, distinct differentiation trajectories of neural progenitor cells were highly associated with AD pathology. Intriguingly, cross-species comparisons among humans, TSs, monkeys, and mice highlighted a greater cellular homogeneity of TSs to primates and humans than to mice. Our extended cross-species analysis by including a direct comparison between human and TS hippocampal tissue under AD conditions uncovered conserved cell types, enriched synaptic biological processes, and elevated excitatory/inhibitory imbalance across species. Cell-cell communication analysis unveiled parallel patterns between AD human and ALP TSs, with both showing reduced interaction strength and quantity across most cell types. Overall, our study provides rich, high-resolution resources on the cellular and molecular landscape of the ALP TS hippocampus, reinforcing the utility of TSs as a robust model for AD research.