Higher p-Cresol sulfate and tumor necrosis factor (TNF)-α levels are associated with cognitive improvement through increased TNF receptor 2 in individuals with mild cognitive impairment: A cross-sectional mediation analysis

Abstract

Background: Neuroinflammation in neurocognitive disorders is driven by the release of tumor necrosis factor (TNF)-α from brain immune cells in response to injury, infection, or p-Cresol sulfate (p-CS)-a metabolite associated with chronic kidney disease and linked to TNF-α activity. However, the underlying mechanisms through which TNF-α and p-CS influence cognitive performance remain unclear.

Objective: This study investigated the impact of TNF-α and p-CS on cognition, focusing on the role of TNF Receptor 2 (TNFR2) in cognitively normal individuals (CN; n = 36), Alzheimer's disease patients (AD; n = 85), and those with mild cognitive impairment (MCI; n = 219).

Methods: Cognitive status was assessed with ADAS-Cog 13, p-CS measured via MxP^® Quant 500, and TNF-α/TNFR2 quantified using Human DiscoveryMAP^®. Mediation analysis explored TNFR2's role in linking p-CS, TNF-α, and cognition, with significance set at p < 0.05 and FDR controlled by the Benjamini-Hochberg method.

Results: The results showed that TNF-α levels were slightly higher in AD than in MCI, while TNFR2 levels were lowest in MCI, higher in CN, and highest in AD. After adjusting for age, gender, and APOE ɛ3/ɛ4 status, higher TNF-α levels were associated with higher TNFR2 levels in both MCI and AD. In MCI, elevated TNFR2 correlated with better cognitive function, indicating a possible neuroprotective role at this stage of cognitive decline. Further analysis revealed that both p-CS and TNF-α contributed to increased TNFR2 levels, which in turn supported cognitive performance.

Conclusions: In short, p-CS and TNF-α may improve cognitive performance via TNFR2 in individuals with MCI.

Keywords: Alzheimer's disease; TNF receptor 2; cognitive performance; mild cognitive impairment; neuroinflammation; p-Cresyl sulfate; tumor necrosis factor-alpha.

Figure 1.

TNF-α, through its receptor TNFR1, plays a crucial role in mediating both inflammation and apoptosis, which contribute to neurodegeneration in the brain. Upon TNF-α binding to TNFR1, the receptor recruits the adaptor protein TRADD, which then activates caspase-8. This activation triggers a cascade leading to the activation of caspase-3, a key mediator of apoptosis, resulting in cell death. In addition, TRADD activates TRAF2, which recruits cIAPs (cellular inhibitors of apoptosis proteins) to inhibit apoptotic signals and simultaneously activates the NF-κB pathway, a central regulator of inflammatory responses. TRAF1, another adaptor protein associated with TNFR1, activates the MEKK1/4 kinase complex and the JNK pathway, further promoting inflammation and apoptosis. These pathways collectively enhance neuroinflammation and contribute to the loss of neurons and tissue integrity in neurodegenerative diseases. In contrast, signaling through TNFR2 leads to a more protective and reparative response in brain cells. Upon TNF-α binding to TNFR2, the receptor recruits TRAF2, which then activates IKK (IκB kinase) and NIK (NF-κB-inducing kinase). These activations stimulate the NF-κB and MAPK pathways, which are involved in promoting cell survival, proliferation, and tissue regeneration. This signaling is critical for protecting neuronal cells from damage, supporting neurogenesis, and facilitating tissue repair. Therefore, while TNFR1-mediated signaling promotes apoptosis and inflammation, TNFR2 activation plays a protective role, contributing to neuroprotection and tissue regeneration. This balance between TNFR1 and TNFR2 signaling represents a complex mechanism governing the response to neuroinflammation and neuronal damage in the brain.