Authors: Babić Leko, Mirjana | Nikolac Perković, Matea | Klepac, Nataša | Švob Štrac, Dubravka | Borovečki, Fran | Pivac, Nela | Hof, Patrick R. | Šimić, Goran
Article Type: Research Article
Abstract: The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O -methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are …associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181 , p-tau199 , and p-tau231 ), amyloid-β42 (Aβ42 ), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t -tau and p -tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p -tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD. Show more
Keywords: Alzheimer’s disease, biomarkers, COMT, DBH, dopamine, MAOB, noradrenaline, polymorphisms
DOI: 10.3233/JAD-190991
Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 135-145, 2020
Authors: Babić Leko, Mirjana | Nikolac Perković, Matea | Klepac, Nataša | Štrac, Dubravka Švob | Borovečki, Fran | Pivac, Nela | Hof, Patrick R. | Šimić, Goran
Article Type: Research Article
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-1 α –889C/T (rs1800587), IL-1 β–1473G/C (rs1143623), IL-6 –174C/G (rs1800795), IL-10 –1082G/A (rs1800896), and TNF α –308A/G (rs1800629) polymorphisms with AD. Objective: We aimed to investigate whether people with certain IL-1 α , IL-1 β, IL-6 , IL-10 , and TNF α 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 TNF α –308A/G genotypes, and in carriers of a G allele in IL-1 β –1473C/G and IL-6 –174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1 β –1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1 β –1473C/G, GC IL-6 –174C/G, and GG TNF α –308A/G genotype. Conclusion: These results suggest that persons carrying certain genotypes in IL10 (–1082G/A), IL1 β (1473C/G), IL6 (–174C/G), and TNFIα (–308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD. Show more
Keywords: Alzheimer’s disease, biomarkers, IL-10, IL-1, IL-6, inflammation, polymorphisms, TNFα
DOI: 10.3233/JAD-200056
Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1029-1047, 2020
Authors: Babić Leko, Mirjana | Jurasović, Jasna | Nikolac Perković, Matea | Španić, Ena | Sekovanić, Ankica | Orct, Tatjana | Lukinović Škudar, Vesna | Bačić Baronica, Koraljka | Kiđemet-Piskač, Spomenka | Vogrinc, Željka | Pivac, Nela | Borovečki, Fran | Hof, Patrick R. | Šimić, Goran
Article Type: Research Article
Abstract: Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE ). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) …patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro . Show more
Keywords: Alzheimer’s disease, apolipoprotein E, copper, metals, mild cognitive impairment, zinc
DOI: 10.3233/JAD-210158
Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 661-672, 2021