The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

Abstract

Background. Neuroinflammation-induced phosphorylated Tau (p-Tau) deposition in central nervous system contributes to neurodegenerative disorders. Propofol possesses neuroprotective properties. We investigated its impacts on tumor necrosis factor-α (TNF-α)-mediated p-Tau deposition in neurons. Methods. Mouse hippocampal neurons were exposed to propofol followed by TNF-α. Cell viability, p-Tau, mitophagy, reactive oxygen species (ROS), NOD-like receptor protein 3 (NLRP3), antioxidant enzymes, and p62/Keap1/Nrf2 pathway were investigated. Results. TNF-α promoted p-Tau accumulation in a concentration- and time-dependent manner. TNF-α (20 ng/mL, 4 h) inhibited mitophagy while increased ROS accumulation and NLRP3 activation. It also induced glycogen synthase kinase-3β (GSK3β) while inhibited protein phosphatase 2A (PP2A) phosphorylation. All these effects were attenuated by 25 μM propofol. In addition, TNF-α-induced p-Tau accumulation was attenuated by ROS scavenger, NLRP3 inhibitor, GSK3β inhibitor, or PP2A activator. Besides, compared with control neurons, 100 μM propofol decreased p-Tau accumulation. It also decreased ROS and NLRP3 activation, modulated GSK3β/PP2A phosphorylation, leaving mitophagy unchanged. Further, 100 μM propofol induced p62 expression, reduced Keap1 expression, triggered the nuclear translocation of Nrf2, and upregulated superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) expression, which was abolished by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Consistently, the inhibitory effect of 100 μM propofol on ROS and p-Tau accumulation was mitigated by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Conclusions. In hippocampal neurons, TNF-α inhibited mitophagy, caused oxidative stress and NLRP3 activation, leading to GSK3β/PP2A-dependent Tau phosphorylation. Propofol may reduce p-Tau accumulation by reversing mitophagy and oxidative stress-related events. Besides, propofol may reduce p-Tau accumulation by modulating SOD and HO-1 expression through p62/Keap1/Nrf2 pathway.

Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model

“…Akhtar et al stated that neuroinflammation was the core feature of neurodegeneration [ 2 ]. Moreover, TNF-α disrupted neuronal mitophagy, increased oxidative stress, triggered inflammation, dysregulated GSK-3 β activity, and promoted p-Tau accumulation [ 63 ]. Further, other studies stated that neurodegeneration in patients with T2DM could be considerably lowered by targeting cytokines, cytokine receptors, and nuclear transcription factors linked to inflammation, like IL-6 and TNF- α, alone or in combination [ 48 ].…”

Crucial role of autophagy in propofol-treated neurological diseases: a comprehensive review

“…Conversely, Chen et al (2013) demonstrated that post-conditioning with propofol after hypoxia treatment can effectively inhibit H/R-induced apoptosis and autophagy in HUVECs by inhibiting PARP cleavage, up-regulating Bcl-2, down-regulating Bax, and preventing the transformation from LC3-I to LC3-II. Zhang et al (2022) also proved the neuroprotective properties of propofol. They found that propofol reduces neuronal damage caused by TNF-α-mediated p-tau deposition via knocking down p62, over-expressing Keap1, or inhibiting Nrf2 through p62/Keap1/Nrf2 pathway.…”