PT  - JOURNAL ARTICLE
AU  - Lei, Chenxu
AU  - Zhang, Bocheng
AU  - Yamaguchi, Junji
AU  - Tamura, Risako
AU  - Cao, Xingyu
AU  - Liu, Yunhui
AU  - Seki, Masahide
AU  - Suzuki, Yutaka
AU  - Suzuki, Kuninori
AU  - Tanida, Isei
AU  - Uchiyama, Yasuo
AU  - Hisatsune, Tatsuhiro
TI  - Impact of astrocytic C3-production on neuronal mitochondrial dysfunction in tauopathy mouse models
AID  - 10.1101/2024.11.12.622892
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.11.12.622892
4099  - http://biorxiv.org/content/early/2024/11/30/2024.11.12.622892.short
4100  - http://biorxiv.org/content/early/2024/11/30/2024.11.12.622892.full
AB  - Neuronal mitochondrial dysfunction is associated with cognitive decline in neurodegenerative disorders such as Alzheimer’s Disease (AD). In this study, multiple pieces of evidence proved that phosphorylated tau (p-Tau) caused mitochondrial swelling and dysfunction in neurons. In a novel in vitro newborn neurons culture system, we discovered mitochondrial swelling and dysfunction were associated with increased p-Tau, leading to necroptosis activation, which was induced by Complement C3 (C3) produced from activated astrocytes. In the in vivo tauopathy mouse models, the effects of astrocytic C3 on tau-associated mitochondrial dysfunction and necroptosis were also discovered in hippocampal newborn neurons, and we directly showed that p-Tau aggregation was associated with mitochondria swelling in the hippocampal neurons by electron microscopy analysis. In addition, we proved the ability of compound anserine, which can block Tak1-Ikk dependent NF-κB activation, to further down-regulate astrocytic C3 production and alleviate neuronal mitochondrial dysfunction in vitro and in vivo, respectively. Down-regulation of astrocyte C3-production by anserine could also rescue mortality as well as cognitive and motor functions. Our findings first reported the contribution of p-Tau on neuronal mitochondrial dysfunction and proposed the therapies that down-regulate astrocytic C3 production have a potential role in alleviating this neurotoxic effect.Competing Interest StatementThe authors have declared no competing interest.