Neurodegenerative Disease atlas

Neurodegenerative diseases, despite diverse etiologies, exhibit converging pathological and molecular features, suggesting shared pathogenic mechanisms. Here, we constructed a cross-disease single-cell transcriptomic atlas of the human central nervous system by integrating data from over 1.4 million cells across 14 studies encompassing eight neurodegenerative diseases. This atlas revealed consistent alterations in cellular composition and cell type-specific transcriptional programs. Genetic enrichment analysis linking risk loci to cell-type-specific regulatory networks identified microglia as central mediators of shared susceptibility. We further delineated two microglial states – lipid-associated microglia (LAM) and PTPRG-high microglia (PHM) – that were significantly expanded across multiple human neurodegenerative diseases. To extend these findings, we generated a mouse microglial atlas from six independent disease models, comprising 335,236 microglia. Despite species differences, cross-species integration uncovered functionally conserved microglial states, particularly stress- and ribosome-associated subpopulations. Notably, the LAM signature gene GPNMB was expanded in human diseases, while mouse Gpnmb was upregulated in disease models. Functional experiments demonstrated that GPNMB overexpression in human microglial cells exerts anti-inflammatory effects. Together, this cross-disease and cross-species resource establishes a framework for understanding conserved microglial responses in neurodegeneration and opens new avenues for therapeutic strategies targeting shared microglial pathways across disorders.