Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway
| Autor: | Dana S.M. Wong, Siwen Li, Christopher Bohm, Yahyah Aman, Yalun Zhang, Ming Yue, Yizhen Jia, Evandro Fei Fang, Paul E. Fraser, Binbin Wang, Ekaterina Rogaeva, Dong-Yan Jin, Qiuju Yuan, You-Qiang Song, Kin Chiu, Peter St George-Hyslop, CT Ng, Yi Zhang, Wing-Hin Chau, Zhi-Gang Zhang, Jennifer K. Griffin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
PAX6 Transcription Factor Tau protein Hyperphosphorylation Mice Transgenic tau Proteins Biology Mice Alzheimer Disease Cyclin-dependent kinase mental disorders Animals Humans E2F1 Phosphorylation Transcription factor Cells Cultured Amyloid beta-Peptides Brain Cell cycle Peptide Fragments Cell biology Mice Inbred C57BL HEK293 Cells biology.protein Neurology (clinical) PAX6 Signal transduction Signal Transduction |
| Zdroj: | Brain. 144:2759-2770 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awab134 |
| Popis: | The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|