Plasma Cytokines Profile in Subjects with Alzheimer’s Disease: Interleukin 1 Alpha as a Candidate for Target Therapy
AbstractBackground: Alzheimer’s disease (AD) is the main cause of the neurodegenerative disorder, which is not detected unless the cognitive deficits are manifested. An early prediagnostic specific biomarker preferably detectable in plasma and hence non-invasive is highly sought-after. Various hypotheses refer to AD, with amyloid-beta (Aβ) being the most studied hypothesis and inflammation being the most recent theory wherein pro-and anti-inflammatory cytokines are the main culprits. Materials and Methods: In this study, the cognitive performance of AD patients (n=39) was assessed using mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating (CDR). Their neuropsychiatric symptoms were evaluated through neuropsychiatric inventory–questionnaire (NPI-Q). Moreover, plasma levels of routine biochemical markers, pro-/anti-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1 α (IL-1α), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12p70, IL-10, Interferon-gamma, chemokines, including prostaglandin E2 (PGE-2), monocyte chemoattractant protein-1, interferon gamma-induced protein 10, Aβ peptide species (42, 40) and Transthyretin (TTR) were measured. Results: Our results revealed that Aβ 42/40 ratio and TTR were correlated (r=0.367, P=0.037). IL-1α was directly correlated with ADAS-cog (r=0.386, P=0.017) and Aβ 40 (r=0.379, P=0.019), but was inversely correlated with IL-4 (r=-0.406, P=0.011). Negative correlations were found between MMSE and PGE2 (r=-0.405, P=0.012) and TNF-α/ IL-10 ratio (r=-0.35, P=0.037). CDR was positively correlated with both PGE2 (r=0.358, P=0.027) and TNF-α (r=0.416, P=0.013). There was a positive correlation between NPI-caregiver distress with CDR (r=0.363, P=0.045) and ADAS-cog (r=0.449, P=0.019). Conclusion: Based on the observed correlation between IL-1α, as a clinical moiety, and ADAS-cog, as a clinical manifestation of AD, anti-IL-1α therapy in AD could be suggested. [GMJ.2021;10:e1974]
Reitz C, R Mayeux. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol. 2014; 88(4): 640-51.
Dourlen P. The new genetic landscape of Alzheimer's disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol. 2019; 138(2): 221-36.
Volpato D, U Holzgrabe. Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer's Disease. Molecules. 2018; 23(12): 3230.
Evin G, A Weidemann. Biogenesis and metabolism of Alzheimer's disease Abeta amyloid peptides. Peptides. 2002; 23(7): 1285-97.
Yoon S S, S A Jo. Mechanisms of Amyloid-beta Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease. Biomol Ther (Seoul). 2012; 20(3): 245-55.
Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006; 12(9): 1005-15.
Heneka M T. Neuroinflammation in Alzheimer's disease. The Lancet Neurology. 2015; 14(4): 388-405.
Gonçalves N P, P Vieira, M J Saraiva. Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis. Amyloid. 2014; 21(3): 175-84.
Swardfager W. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry. 2010; 68(10): 930-41.
Hickman S E, E K Allison, J El Khoury. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008; 28(33): 8354-60.
Belkhelfa M. IFN-gamma and TNF-alpha are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res. 2014; 34(11): 839-47.
Shaftel S S, W S Griffin, M K O'Banion. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008; 5: 7.
Dursun E. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. J Neuroimmunol. 2015; 283: 50-7.
Italiani P. Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression? J Neuroimmunol. 2018; 15(1): 1-12.
Lee S C. Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol. 1993; 150(7): 2659-67.
Cojocaru I M. Study of interleukin-6 production in Alzheimer's disease. Rom J Intern Med. 2011; 49(1): 55-8.
Heneka M T. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14(4): 388-405.
Leung R. Inflammatory proteins in plasma are associated with severity of Alzheimer's disease. PLoS One. 2013; 8(6): e64971.
D'Anna L. Serum Interleukin-10 Levels Correlate with Cerebrospinal Fluid Amyloid Beta Deposition in Alzheimer Disease Patients. Neurodegener Dis. 2017; 17(4-5): 227-34.
Johansson J U. Inflammatory Cyclooxygenase Activity and PGE2 Signaling in Models of Alzheimer's Disease. Curr Immunol Rev. 2015; 11(2): 125-31.
Hayney M S. Serum IFN-gamma-induced protein 10 (IP-10) as a biomarker for severity of acute respiratory infection in healthy adults. J Clin Virol. 2017; 90: 32-7.
Sun Y X. Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2003; 16(3): 136-44.
Galimberti D.Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease. Neurobiol Aging. 2006; 27(12): 1763-8.
Lee W J. Plasma MCP-1 and Cognitive Decline in Patients with Alzheimer's Disease and Mild Cognitive Impairment: A Two-year Follow-up Study. Sci Rep. 2018; 8(1): 1280.
Zheng C. X W Zhou. J Z Wang. The dual roles of cytokines in Alzheimer's disease: update on interleukins, TNF-alpha, TGF-beta and IFN-gamma. Transl Neurodegener. 2016; 5: 7.
Wang W Y. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015; 3(10): 136.
Guzman-Martinez L. Neuroinflammation as a Common Feature of Neurodegenerative Disorders. Front Pharmacol. 2019; 10: 1008.
Bu X L. Blood-derived amyloid-beta protein induces Alzheimer's disease pathologies. Mol Psychiatry. 2018; 23(9): 1948-56.
van Oijen. Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 2006; 5(8): 655-60.
Graff-Radford N R. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol. 2007; 64(3): 354-62.
Fandos N, et al. Plasma amyloid beta 42/40 ratios as biomarkers for amyloid beta cerebral deposition in cognitively normal individuals.Amst. 2017; 8: 179-87.
Gloeckner S F, et al. Quantitative analysis of transthyretin, tau and amyloid-beta in patients with dementia. J Alzheimers Dis. 2008; 14(1): 17-25.
Hansson S F, et al. Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients. J Alzheimers Dis. 2009; 16(2): 389-97.
Velayudhan L, et al. Plasma transthyretin as a candidate marker for Alzheimer's disease. J Alzheimers Dis. 2012; 28(2): 369-75.
Fedosov S N. Biochemical markers of vitamin B12 deficiency combined in one diagnostic parameter: the age-dependence and association with cognitive function and blood hemoglobin. Clin Chim Acta. 2013; 422: 47-53.
Siuda J, et al. From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Neurol Neurochir Pol. 2009; 43(4): 321-9.
Smith, A D, H Refsum. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016; 36: 211-39.
Blennow K, et al. Amyloid biomarkers in Alzheimer's disease. Trends Pharmacol Sci. 2015; 36(5): 297-309.
Agyare E K, et al. Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits. J Control Release. 2014; 185: 121-9.
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