IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology

Article type: Research Article

Authors: Babić Leko, Mirjana^a | Nikolac Perković, Matea^b | Klepac, Nataša^c | Štrac, Dubravka Švob^b | Borovečki, Fran^c | Pivac, Nela^b | Hof, Patrick R.^d | Šimić, Goran^{a; *}

Affiliations: [a] Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia | [b] Department of Molecular Medicine, Institute Ruđer Bošković, Zagreb, Croatia | [c] Department of Neurology, University Hospital Centre Zagreb, Zagreb, Croatia | [d] Nash Family Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Correspondence: [*] Correspondence to: Goran Šimić, Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia. E-mail: [email protected].

Abstract: Background:Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α –889C/T (rs1800587), IL-1β–1473G/C (rs1143623), IL-6 –174C/G (rs1800795), IL-10 –1082G/A (rs1800896), and TNFα –308A/G (rs1800629) polymorphisms with AD. Objective:We aimed to investigate whether people with certain IL-1α, IL-1β, IL-6, IL-10, and TNFα genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p-tau199), and Thr 231 (p-tau231), and visinin-like protein 1 (VILIP-1). Methods:The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. Results:A significant increase in p-tau CSF levels was found in patients with the AA IL-10 –1082G/A and GG TNFα –308A/G genotypes, and in carriers of a G allele in IL-1β –1473C/G and IL-6 –174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β –1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β –1473C/G, GC IL-6 –174C/G, and GG TNFα –308A/G genotype. Conclusion:These results suggest that persons carrying certain genotypes in IL10 (–1082G/A), IL1β (1473C/G), IL6 (–174C/G), and TNFIα (–308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

Keywords: Alzheimer’s disease, biomarkers, IL-10, IL-1, IL-6, inflammation, polymorphisms, TNFα

DOI: 10.3233/JAD-200056

Journal: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1029-1047, 2020