PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis

Cell & Bioscience

Research

D. Eric Anderson¹  Yihong Ye²  Peng Wang² 

[1] Advanced Mass Spectrometry Core, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, 20892, Bethesda, MD, USA;Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, 20892, Bethesda, MD, USA;

关键词: tau;    Integrin;    αV/β1;    PI3 kinase/PI3K;    AKT;    Focal adhesion kinase/FAK;    Astrogliosis;    Alzheimer’s disease/AD;    Tauopathy;    Neuroinflammation;   

DOI  :  10.1186/s13578-023-01128-x

 received in 2023-08-11, accepted in 2023-09-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMicrotubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro-inflammatory state via integrin activation, causing them to release unknown neurotoxic factors.ResultsHere, we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors.ConclusionsThese findings reveal an unexpected function for PI3K-AKT in tauopathy-associated reactive astrogliosis, which may be a promising target for anti-inflammation-based Alzheimer’s therapy.

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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