DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Hao Chen; Li Fan; Qi Guo; Man Ying Wong; Jingjie Zhu; Nessa R. Foxe; Winston T. Wang; Aviram Nessim; Gillian Carling; Bangyan Liu; Chloe Lopez-Lee; Yige Huang; Sadaf Amin; Tark Patel; Sue‐Ann Mok; Won-Min Song; Bin Zhang; Shiaoching Gong; Qin Ma; Hongjun Fu; Li Gan; Wenjie Luo

doi:10.1186/s13024-025-00903-3

NeuroscienceMolecular NeurodegenerationDec 2, 2025

Peer-reviewed journal article

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Hao Chen iD, Li Fan iD, Qi Guo iD, Man Ying Wong iD, Jingjie Zhu iD, Nessa R. Foxe, Winston T. Wang iD, Aviram Nessim iD, Gillian Carling iD, Bangyan Liu, Chloe Lopez-Lee iD, Yige Huang iD, Sadaf Amin iD, Tark Patel, Sue‐Ann Mok iD, Won-Min Song, Bin Zhang iD, Shiaoching Gong iD, Qin Ma iD, Hongjun Fu iD, Li Gan iD, Wenjie Luo iD

Abstract

Pathogenic tau accumulation fuels neurodegeneration in Alzheimers disease (AD). Enhancing aging brains resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

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