RT Journal Article
SR Electronic
T1 Impact of astrocytic C3-production on neuronal mitochondrial dysfunction in tauopathy mouse models
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.11.12.622892
DO 10.1101/2024.11.12.622892
A1 Lei, Chenxu
A1 Zhang, Bocheng
A1 Yamaguchi, Junji
A1 Tamura, Risako
A1 Cao, Xingyu
A1 Liu, Yunhui
A1 Seki, Masahide
A1 Suzuki, Yutaka
A1 Suzuki, Kuninori
A1 Tanida, Isei
A1 Uchiyama, Yasuo
A1 Hisatsune, Tatsuhiro
YR 2024
UL http://biorxiv.org/content/early/2024/11/30/2024.11.12.622892.abstract
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.