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

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.

Mechanism of Zhinao Capsule in Treating Alzheimer’s Disease Based on Network Pharmacology Analysis and Molecular Docking Validation

“…Neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis [ 46 ]. Accumulating evidence shows an important link between TNF and AD, and the TNF- α signaling pathway predominantly mediates inflammatory and proapoptotic signaling pathways [ 47 ]. In addition, TNF is involved in systemic inflammation; TNF and TNF receptor type 1 participate in neuroinflammation associated with AD and are also involved in amyloid- β formation [ 48 ].…”

Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease

“…Clinical studies have shown that overactivated M1 phenotype microglia can cause neuronal disability, damage and degeneration; and play an important role in cerebrovascular and neurodegenerative diseases and neurodevelopmental and mental disorders [ 16 , 45 , 46 , 47 ]. Microglia secrete proinflammatory factors including Interleukin-1β [ 26 , 27 , 48 , 49 ], Interleukin-6 [ 49 , 50 , 51 ] and TNFα [ 49 , 52 , 53 ], along with an increased production of ROS [ 54 , 55 , 56 ], which can cause damage to the surrounding neuronal cells. In AD, M1 phenotype microglia that secrete pro-inflammatory factors maintain the neuroinflammatory microenvironment and continuously aggravate neuronal damage.…”

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

“…RIPK3 and MLKL are important for necroptosis activation [58,[152][153][154][155]158,165,166]. TNF-α/TNFR1-induced necroptosis occurs in several neurodegenerative diseases of the CNS, such as multiple sclerosis (MS), Parkinson's disease and Alzheimer's disease [156,[167][168][169][170]. After an ischaemic stroke, perivascular microglia-induced endothelial necroptosis leading to disruption of the bloodbrain barrier requires TNF-α to act on its receptor TNFR1 [57].…”