THE INFLUENCE OF THE APOEε4 ALLELE ON PRO-INFLAMMATORY CYTOKINE LEVELS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH ALZHEIMER’S DISEASE

Jelena Bašić, Vuk Milošević, Branka Đorđević, Nikola Stefanović, Vladana Stojiljković, Tatjana Jevtović Stoimenov, Ivana Stojanović

DOI Number
https://doi.org/10.22190/FUMB231012006B
First page
037
Last page
041

Abstract


Single nucleotide polymorphisms (SNPs) rs429358 and rs7412, the most commonly investigated variants in the apolipoprotein E gene (APOE) are crucial for APOEε4 carrier status determination. However, their association with inflammatory cytokine levels in patients with dementia due to Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the influence of the APOEε4 allele on pro-inflammatory cytokine levels in the cerebrospinal fluid of patients with AD dementia. The research was conducted on 36 patients with probable dementia due to AD. APOE rs429358 and rs7412 were analyzed using the Real-Time PCR method with allele-specific TaqMan assays, followed by the analysis of APOEε4 allele carrier status. Patients carrying at least one APOEε4 allele were assigned as APOEε4+. Core biomarkers (Aβ42/40 ratio, t-Tau, p-Tau levels), as well as pro-inflammatory cytokine (Tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b)) levels, were determined in the patient’s cerebrospinal fluid (CSF) using Enzyme-linked Immunosorbent Assay (ELISA). Seventeen patients (47.22%) were assigned as APOEε4+. CSF TNF-α levels were significantly higher in APOEε4+ AD dementia patients in comparison to APOEε4- patients (p<0.001), while no significant differences in IL-1b levels between these two groups were obtained. Correlation analysis showed that TNF-α negatively correlated with the Aβ42/40 ratio (p=0.033), while positive correlation with t-Tau and p-Tau was observed (p=0.001, p=0.015, respectively). These findings highlight the potential significance of TNF-α in the context of APOEε4 positivity and its implications in AD pathology.


Keywords

Apolipoprotein E ε4, Alzheimer's disease, IL-1β, TNF- α

Full Text:

PDF

References


Nichols E, Szoeke CE, Vollset SE, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(1):88–106.

Nichols E, Steinmetz JD, Vollset SE, et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2022; 7(2):e105–125.

Frisoni GB, Altomare D, Thal DR, et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci 2022; 23(1):53–66.

Ando K, Houben S, Homa M, et al. Alzheimer’s disease: tau pathology and dysfunction of endocytosis. Front Mol Neurosci 2021; 13:583755.

Patel KP, Wymer DT, Bhatia VK, Duara R, Rajadhyaksha CD. Multimodality imaging of dementia: clinical importance and role of integrated anatomic and molecular imaging. Radiographics 2020; 40(1):200–22.

McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3):263–9.

Jack Jr CR, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4):535–62.

Prins S, de Kam ML, Teunissen CE, Groeneveld GJ. Inflammatory plasma biomarkers in subjects with preclinical Alzheimer’s disease. Alzheimers Res Ther 2022; 14(1):1–9.

Troutwine BR, Hamid L, Lysaker CR, Strope TA, Wilkins HM. Apolipoprotein E and Alzheimer’s disease. Acta Pharm Sin B 2022; 12(2):496–510.

Milošević V, Malobabić M, Stojanović I, Bašić J. Importance of a functional measure in the evaluation of patients in a memory clinic: Validation of the Serbian version of the Amsterdam instrumental activities of daily living questionnaire. Clin Neurol Neurosurg 2022; 214:107165.

Milošević V, Malobabić M, Antić E, Trenkić AA, Stojanov D, Bašić J. Assessment of the instrumental activities of daily living in mild cognitive impairment and dementia due to alzheimer’s disease: diagnostic accuracy of the serbian version of the amsterdam iadl questionnaire. Facta Univ Ser Med Biol 2022; 24(2):35–9.

Bašić J, Milošević V, Đorđević B, et al. Association of the apolipoprotein E ε4 allele in a Serbian population with Alzheimer’s dementia. Arch Biol Sci 2023; 75(3):319–25.

Angiulli F, Conti E, Zoia CP, et al. Blood-based biomarkers of neuroinflammation in Alzheimer’s disease: A central role for periphery? Diagnostics 2021; 11(9):1525.

de la Monte SM, Tong M, Hapel AJ. Concordant and Discordant Cerebrospinal Fluid and Plasma Cytokine and Chemokine Responses in Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease. Biomedicines 2023; 11(9):2394.

Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 2019; 101(5):820–38.

Bachmeier C, Shackleton B, Ojo J, Paris D, Mullan M, Crawford F. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. Neuromolecular Med 2014; 16:686–96.

Iannucci J, Sen A, Grammas P. Isoform-specific effects of apolipoprotein E on markers of inflammation and toxicity in brain glia and neuronal cells in vitro. Curr Issues Mol Biol 2021; 43(1):215–25.

Wang C, Fan L, Khawaja RR, et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun 2022; 13(1):1969.

Arnaud L, Benech P, Greetham L, et al. APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation. Cell Rep 2022; 40(7):111200.

Wang C, Najm R, Xu Q, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med 2018; 24(5):647–57.

Friedberg JS, Aytan N, Cherry JD, et al. Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype. Sci Rep 2020; 10(1):2924.

Abe K, Chiba Y, Ide K, et al. Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer’s Disease Neuroimaging Initiative Database. J Prev Alzheimers Dis. 2022; 9(2):331–7.

Contreras JA, Aslanyan V, Albrecht DS, Mack WJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Pa J. Higher baseline levels of CSF inflammation increase risk of incident mild cognitive impairment and Alzheimer’s disease dementia. Alzheimers Dement Diagn Assess Dis Monit. 2022; 14(1):e12346.




DOI: https://doi.org/10.22190/FUMB231012006B

Refbacks

  • There are currently no refbacks.


© University of Niš, Serbia
Creative Commons licence CC BY-NC-ND
ISSN 0354-4699 (Print)
ISSN 2406-050X (Online)