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

TitleDAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.
Publication TypeJournal Article
Year of Publication2023
AuthorsChen H, Fan L, Guo Q, Wong MYing, Yu F, Foxe N, Wang W, Nessim A, Carling G, Liu B, Lopez-Lee C, Huang Y, Amin S, Mok S-A, Song W-M, Zhang B, Ma Q, Fu H, Gan L, Luo W
JournalRes Sq
Date Published2023 Oct 26
Abstract

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's 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.

DOI10.21203/rs.3.rs-3454358/v1
Alternate JournalRes Sq
PubMed ID37961627
PubMed Central IDPMC10635319
Grant ListU54 NS100717 / NS / NINDS NIH HHS / United States
R01 AG074541 / AG / NIA NIH HHS / United States
R01 AG075092 / AG / NIA NIH HHS / United States
R01 AG072758 / AG / NIA NIH HHS / United States
R01 AG064239 / AG / NIA NIH HHS / United States