IL-8 and MCP-1 Impact on Tau Phosphorylation and Phosphatase Activity

Abstract

Background: Chronic inflammation is a feature of Alzheimer´s disease (AD), resulting in excessive production of inflammatory mediators that can lead to neuroinflammation, contributing to alterations in Ab production and deposition as Senile Plaques (SPs), and to neurofibrillary tangles (NFTs) formation, due to hyperphosphorylated Tau protein. Objective: This work addressed the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two chemokines, on Tau phosphorylation; also evaluated the chemokines’ levels in plasma using samples from a regional cohort. Method: Human neuronal SH-SY5Y cells exposed to IL-8 and MCP-1 chemokines were monitored for their protein and phosphorylated protein levels by western blotting analysis. A serine/threonine protein phosphatase (PPs) activity assay was employed to monitor PPs activity. Subsequently, flow cytometry was used to monitor chemokines levels in plasma samples from individuals with cognitive deficits. Results: Chemokines’ exposure resulted only in minor cytotoxicity effects on SH-SY5Y, and in increased Tau phosphorylation, particularly at the S396 residue. Tau phosphorylation correlated with PPs inhibition and was consistent with GSK3b phosphorylation-mediated inhibition. Subsequent analysis of plasma from individuals with cognitive deficits showed that IL-8 levels were decreased. Conclusion: Data shows that both chemokines tested can exert an effect on GSK3b phosphorylation and modulate PPs activity, potentially resulting in increased Tau phosphorylation and subsequent NFTs formation. One can deduce that increased chemokines stimulation during chronic inflammation can exacerbate this event. The work contributes to a better understanding of the mode of action of these chemokines on AD pathogenesis and opens novel research avenues.

Association between Periodontal Disease and Cognitive Impairment in Adults

“…The expression of IL-8, a proinflammatory cytokine commonly degraded by P. gingivalis gingipain proteases [ 47 ], has been shown to be differentially altered in AD and dementia. Similar to the findings presented by Montoya et al, IL-8 is downregulated in dementia and cognitive impairment [ 51 , 52 ]. However, IL-8 is usually upregulated in AD, favoring neuroinflammation [ 53 ].…”

Association between Periodontal Disease and cognitive impairment in Adults

“…The expression of IL-8, a proinflammatory cytokine commonly degraded by P. gingivalis gingipain proteases [51], has been shown to be differentially altered in AD and dementia. Similar to the findings presented by Montoya et al, IL-8 is downregulated in dementia and cognitive impairment [55] [56]; however, IL-8 is usually upregulated in AD favoring neuroinflammation [57]. As indicated by Montoya et al, one limitation of their study was the fact that only a single measurement of proinflammatory biomarkers had been performed [43], thus it is difficult to pinpoint whether the recorded outcome of cognitive impairment is a definitive result of the downregulation of IL-8 by P. gingivalis, especially since no information was provided regarding the final diagnosis of each patient, i.e.…”

Blood and CSF chemokines in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis

“…When in vitro stimulated with Aβ, microglia, astrocytes, and neurons were all capable of producing CXCL8. It was reported that IL-8 could affect GSK3β phosphorylation and modulate protein phosphatase activity in vitro, resulting in enhanced Tau phosphorylation [ 105 ]. A study [ 106 ] found that CXCL8 levels in AD brain were considerably greater than those in age-matched controls.…”