PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau vs OPN]
Microtubule-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. Here 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. These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated astrogliosis and a target for anti-inflammation-based Alzheimer's therapy. Overall design: Primary astrocytes isolated from wild type C57BL/6J mice were treated with Tau PFF together with FAK inhibitor PF-562271, AKT inhibitor MK2202, PI3K inhibitor PI103, Nfkb inhibitor PDTC or FAK inhibitor PF271 for 6 hours. Cells were then collected and total RNA was extracted for RNA sequencing.