Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer’s disease

Summary Alzheimer’s disease (AD) arises from pathological interactions among diverse brain cell types, but cell-specific proteomic changes remain underexplored. Here, we present deep proteomic profiling of sorted or proximity-labeled brain cells from AD mouse models (5xFAD and App NL-G-F ) at multiple ages, quantifying 13,411 proteins in microglia (three subtypes), astrocytes, oligodendrocyte precursor cells, and neurons. We identified 3,028 differentially abundant proteins across these cell types, the majority of which were not detected in bulk proteomic datasets, and constructed cell type-specific networks to define functional modules and hub proteins. Comparison with transcriptomic data revealed that ∼30% of proteomic changes are RNA-independent. Further analyses uncovered cross-cell type signaling proteins conserved in human AD brains, such as pleiotrophin (Ptn), which is transcriptionally enriched in astrocytes but accumulates in microglia. Importantly, recombinant PTN directly activates induced microglia-like (iMG) human cells. Thus, these findings provide a comprehensive cell type-resolved proteomic atlas of AD models, highlighting novel intra- and intercellular signaling events. Highlights A high-resolution cell type-resolved proteomic atlas of Alzheimer’s disease mouse models ∼3,000 cell type-specific protein alterations identified beyond bulk tissue analyses Proteomic profiling of microglial subtypes reveals subtype-specific changes in Alzheimer’s disease Astrocyte-microglia signaling is highlighted and validated through PTN-mediated interactions