| First Author | Wang P | Year | 2023 |
| Journal | Cell Biosci | Volume | 13 |
| Issue | 1 | Pages | 179 |
| PubMed ID | 37759245 | Mgi Jnum | J:355508 |
| Mgi Id | MGI:7748933 | Doi | 10.1186/s13578-023-01128-x |
| Citation | Wang P, et al. (2023) PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis. Cell Biosci 13(1):179 |
| abstractText | BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: These 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. |
