| First Author | Xu C | Year | 2021 |
| Journal | Theranostics | Volume | 11 |
| Issue | 19 | Pages | 9452-9469 |
| PubMed ID | 34646380 | Mgi Jnum | J:313643 |
| Mgi Id | MGI:6788517 | Doi | 10.7150/thno.62376 |
| Citation | Xu C, et al. (2021) TNF-alpha-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics 11(19):9452-9469 |
| abstractText | Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5xFAD. We performed brain stereotaxic injection with recombinant TNF-alpha, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-alpha combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-alpha/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-alpha stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-alpha-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-alpha signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD. |
