Dual inhibition of IRAK1/TAK1 signaling in astrocytes reduces accelerated mortality in human APOE4 knock-in APPswe/PSEN1dE9/P301S-Tau triple transgenic mouse model

Reactive astrocytes are associated with the progression of neurodegenerative diseases such as Tauopathies represented by Alzheimer’s disease (AD), particularly in the human APOE4 background. Previous studies using P301S tauopathy model mice have shown the potential contribution of activated astrocytes to tau-associated neurodegeneration and accelerated mortality. However, the impact of Aβ pathology on modulating mortality, astrocyte activation and neurodegeneration in this model remains unclear. We established a novel AD mouse model (E4-3Tg) by crossing P301S-Tau mice with APPswe/PSEN1dE9 mice on human APOE4 knock-in background and compared its phenotypes with the human APOE4 knock-in P301S-Tau (TE4) mouse model. The impact of Aβ in P301S tauopathy mice was evaluated by analyzing survival rate, astrocyte activation, tau-associated neurodegeneration and behavior performance. We also assessed degeneration in mature and immature hippocampal neurons using scanning electron microscopy and RNA-sequencing analysis. Moreover, we suppressed A1 astrocyte activation to evaluate its contribution in the pathology observed in E4-3Tg and TE4 mice. E4-3Tg mice exhibited significantly accelerated mortality, with a median survival of approximately 6.5 months, compared to around 9 months in TE4 mice. At 6.5 months of age, compared to TE4 mice, E4-3Tg mice had already developed prominent A1 astrocyte activation, accompanied by exacerbated tau pathology, neuronal loss, and cognitive impairment. Notably, E4-3Tg mice also showed a marked reduction in hippocampal immature neurons, associated with tau-related mitochondrial dysfunction and cellular senescence, a phenotype absent in TE4 mice even at 9 months of age. Administration of anserine (beta-alanyl-3-methyl-L-histidine), which was demonstrated to be a dual IRAK1/TAK1 inhibitor targeting astrocytes, effectively suppressed A1 astrocyte activation and reduced the accelerated mortality observed in both E4‑3Tg and TE4 mice. Moreover, this protective effect of anserine was accompanied by attenuated tau-associated mitochondrial dysfunction and neuronal loss in both mature and immature hippocampal neurons. Collectively, our findings demonstrated that Aβ pathology accelerates mortality in tauopathy model by promoting A1 astrocyte activation and aggravating tau-associated neurodegeneration. Therapeutic inhibition of astrocytic IRAK1/TAK1 signaling reduced mortality and alleviated tau-associated neurodegeneration, highlighting A1 astrocyte activation as a promising target for reducing accelerated mortality in Alzheimer’s disease.