DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice

作者：Hao Chen, Li Fan, Qi Guo, Man Ying Wong, Jingjie Zhu, Nessa Foxe, Winston 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 · 发表于：Molecular Neurodegeneration · 年份：2025 · DOI：10.1186/s13024-025-00903-3 · 被引用次数：3 · 研究领域：Axon Guidance and Neuronal Signaling、Neurogenesis and neuroplasticity mechanisms、Nerve injury and regeneration

BACKGROUND: Pathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive. METHODS: We investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion. RESULTS: We demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alter...