Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway
- 24 August 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 144 (9), 2759-2770
- https://doi.org/10.1093/brain/awab134
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China (81271226)
- Research Grant Council
- Hong Kong Special Administrative Region (11200218)
- HELSE SøR-ØST (#2017056, #2020001, #2021021)
- Research Council of Norway (#262175, #277813)
- National Natural Science Foundation of China (#81971327)
- Akershus University Hospital Strategic (#269901)
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