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Theranostics 2021; 11(19):9452-9469. doi:10.7150/thno.62376 This issue Cite

Research Paper

TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG

Chong Xu^1#, Jialin Wu^1#, Yiqun Wu¹, Zhichu Ren¹, Yuyuan Yao¹, Guobing Chen², Evandro F. Fang^3,4, Ji Heon Noh⁵, Yong U. Liu⁶, Libin Wei⁷, Xijing Chen⁸, Jian Sima^1✉

1. Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
2. Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
3. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
4. The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway.
5. Department of Biochemistry, Chungnam National University, Daehak-ro 99, Yuseong-gu, Daejeon.
6. Laboratory for Neuroscience in Health and Disease, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
7. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, China.
8. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
#These authors contributed equally to this work.

✉ Corresponding author: J. S. (E-mail: simajianedu.cn).

Abstract

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 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α 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-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α 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-α-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-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.

Keywords: Alzheimer's disease, neuronal necroptosis, TNF-α/TNFR1 signaling, RIPK1/RIPK3/MLKL cascade, autophagic flux, p62, UVRAG

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