Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway

Quintanilla, Rodrigo A; Orellana, Daniel I; González-Billault, Christian; Maccioni, Ricardo B

doi:10.1016/j.yexcr.2004.01.002

Cited by 455Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway

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Quintanilla, Rodrigo A, Orellana, Daniel I, González-Billault, Christian, Maccioni, Ricardo B·2004·Experimental Cell Research

DOI 10.1016/j.yexcr.2004.01.002

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Abstract

Inflammation is a process that has been actively related with the onset of several neurodegenerative disorders including Alzheimer disease (AD). However, the precise implications of inflammatory response for neurodegeneration have not been elucidated. A current hypothesis considers that extracellular insults to neurons could trigger the production of inflammatory cytokines by astrocytes and microglia. These cytokines, namely, interleukin (IL)-1beta, TNFalpha, and IL-6, could affect the normal behavior of neuronal cells. In the present study, we describe the effect of the administration at physiologic doses of one of these cytokines, IL-6, to hippocampal neurons, on the protein kinase pathways as well as on the tau phosphorylation patterns. IL-6-treated neurons exhibited an increase in the amount of anomalously hyperphosphorylated tau protein in epitopes dependent on proline-directed protein kinases (PDPKs). On the basis of our data, the observed increase of tau epitopes of Alzheimer type is explained by an increase of intraneuronal levels of p35 activator and in the activity of the protein kinase cdk5 in response to this cytokine. Further confirmation of cdk5 involvement in this process was based on the findings that inhibition of the kinase activity with butyrolactone-I prevents the appearance of tau of Alzheimer type in IL-6-treated neurons. Additional studies suggest that an increase of cdk5 activity could be mediated by a known signaling cascade described for IL-6 function, namely, the MAPK-p38 signaling pathway. Stimulation of the IL-6 pathway appears to increase the tau epitopes of Alzheimer type, as demonstrated in studies with specific inhibitors. These results support the findings of a pathologic role for IL-6 in the neuroinflammatory response as related with the pathogenesis of neuronal degeneration.

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Prior reports indicate that IL6 can induce tau hyperphosphorylation.
“IL6 was also reported to induce hyperphosphorylation of tau (Quintanilla, et al., 2004).”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as Quintanilla, et al., 2004
Other inflammatory factors such as IL-3, IL-6, IL-18, TNFα, and MIF are involved in tau phosphorylation and/or truncation.
“Other inflammatory factors such as IL-3, IL-6, IL-18, tumor necrosis factor-α (TNFα), and macrophage migration inhibitory factor (MIF) are also found to be involved in tau phosphorylation and/or truncation [166–170].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [168]
Treatment of hippocampal neurons with IL-6 led to tau phosphorylation via cdk5 and p35.
“Conversely, treatment of hippocampal neurons with IL-6 led to tau phosphorylation via cdk5 and p35 [158].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [158]
Proinflammatory cytokines TNFα, IL1β, and IL6 promote tau phosphorylation in neurons.
“First, the proinflammatory cytokines TNFα, IL1 β, and IL6 have been shown to promote tau phosphorylation in neurons (Bhaskar et al., 2010; Kitazawa et al., 2011; Quintanilla et al., 2004).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Quintanilla et al., 2004

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Authors: Quintanilla, R. A., Orellana, D. I., González-Billault, C., & Maccioni, R. B.
Affiliations: CBB (Chile) (CL)
Corresponding author: Maccioni, Ricardo B
ORCID: Quintanilla, Rodrigo A
Orellana, Daniel I
González-Billault, Christian
Maccioni, Ricardo B
Venue: Experimental Cell Research
Publisher: Elsevier BV
Published: 2004-04-15
Volume: 295
Issue: 1
Pages: 245-257
ISSN: 0014-4827 (ISSN-L)
DOI: 10.1016/j.yexcr.2004.01.002
OpenAlex: W2057850192
Cited by: 455
References: 60
Citations by year: 2026: 23 · 2025: 33 · 2024: 33 · 2023: 39 · 2022: 47 · 2021: 46 · 2020: 43 · 2019: 13 · 2018: 18 · 2017: 10 · 2016: 18 · 2015: 19 · 2014: 20 · 2013: 8 · 2012: 12
FWCI: 5.68
Type: journal article
Language: en
Open access: green
americanae.aecid.es
Licence: other-oa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Experimental Cell Research (publishedVersion)
PubMed (publishedVersion)
Americanae (AECID Library) (submittedVersion, other-oa)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Universidad de Chile (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: interleukin-6, tau phosphorylation, Alzheimer's disease, cyclin-dependent kinase 5, p35, proline-directed protein kinases, neuroinflammation, hippocampal neurons, p38 MAPK, butyrolactone I, neurodegeneration, cytokines
MeSH terms: Alzheimer Disease, Animals, Cell Survival, Enzyme Inhibitors, Flavonoids, Hippocampus, Humans, Imidazoles, Nerve Tissue Proteins, Neurons, Phosphorylation, Pyridines, Recombinant Proteins, Interleukin-6, tau Proteins, Rats, Sprague-Dawley, DNA Primers, Cell Culture Techniques, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Rats

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Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway

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