How DAP12 deletion enhances brain resilience in female tauopathy mice.
Microglia selectively expresses DAP12 (DNAX-activation protein 12), which, plays a crucial role in microglial immune responses.
Previously, it was show that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits but the mechanism remains elusive.
The authors in this study show that tau processing in primary microglia is reduced by Dap12 deletion, while, tau pathology increased in female tauopathy mice, with minimal effects on males. However, brain inflammation, synapse loss, and demyelination are reduced by Dap12 deletion indicating enhanced resilience to tau toxicity.
The authors also show that elevated SLIT2 levels and demyelination in tauopathy and is reversed by Dap12 deletion. The author s also found correlation of SLIT2 expression and tau pathology in AD brain tissue. https://sciencemission.com/DAP12-deletion-reduces-neuronal-SLIT2
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.