Abstract:A relationship between Alzheimer's disease (AD) and folate has been reported. Amyloid positron emission tomography (PET) is currently one of the most reliable biomarkers for AD. We investigated the correlation between serum folate levels and amyloid imaging to clarify whether serum folate could be a biomarker for AD. We also examined the usefulness of a combined assessment of serum folate levels and red blood cell hemoglobin content. Apolipoprotein E (APOE) gene polymorphisms were also assessed. Serum folate l… Show more
“…However, idiopathic anemia is a common comorbidity with AD [82], and low hemoglobin associates with greater risk of death among AD patients [83]. On the other hand, in a Japanese study confined solely to dementia patients, subjects had a direct association between greater levels of circulating hemoglobin and brain accumulation of Aβ [84]. Fig.…”
In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.
“…However, idiopathic anemia is a common comorbidity with AD [82], and low hemoglobin associates with greater risk of death among AD patients [83]. On the other hand, in a Japanese study confined solely to dementia patients, subjects had a direct association between greater levels of circulating hemoglobin and brain accumulation of Aβ [84]. Fig.…”
In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.
“…Indeed, many protein biomarkers serve for the evaluation and management of myocardial insults and cardiac remodeling; these include BNP, N-terminal proBNP, C-reactive protein, and Troponin T amongst others [ 50 , 51 ]. In addition, hemoglobin content combined with serum folate levels have been suggested as potential biomarkers for Alzheimer’s disease [ 52 ]. Combined, this would support further investigation into the role for acetylated or deacetylated circulating factors as biomarkers for cardiovascular disease; blood analysis from patients serves as a relatively simple and non-invasive procedure in the clinic.…”
Lysine residues undergo diverse and reversible post-translational modifications (PTMs). Lysine acetylation has traditionally been studied in the epigenetic regulation of nucleosomal histones that provides an important mechanism for regulating gene expression. Histone acetylation plays a key role in cardiac remodeling and function. However, recent studies have shown that thousands of proteins can be acetylated at multiple acetylation sites, suggesting the acetylome rivals the kinome as a PTM. Based on this, we examined the impact of obesity on protein lysine acetylation in the left ventricle (LV) of male c57BL/6J mice. We reported that obesity significantly increased heart enlargement and fibrosis. Moreover, immunoblot analysis demonstrated that lysine acetylation was markedly altered with obesity and that this phenomenon was cardiac tissue specific. Mass spectral analysis identified 2515 proteins, of which 65 were significantly impacted by obesity. Ingenuity Pathway Analysis® (IPA) further demonstrated that these proteins were involved in metabolic dysfunction and cardiac remodeling. In addition to total protein, 189 proteins were acetylated, 14 of which were significantly impacted by obesity. IPA identified the Cardiovascular Disease Pathway as significantly regulated by obesity. This network included aconitate hydratase 2 (ACO2), and dihydrolipoyl dehydrogenase (DLD), in which acetylation was significantly increased by obesity. These proteins are known to regulate cardiac function yet, the impact for ACO2 and DLD acetylation remains unclear. Combined, these findings suggest a critical role for cardiac acetylation in obesity-mediated remodeling; this has the potential to elucidate novel targets that regulate cardiac pathology.
“…Therefore, studies that investigate multiple biomarkers may allow increased precision in the prediction of AD risk and could benefit individuals and communities alike. Interestingly, a recent small study (n = 17) using a ROC curve analysis found SF and red blood cell haemoglobin to be useful biomarkers of Aβ accumulation in the brain with more sensitivity and specificity than APOE genotype or folate alone (18). Future research targeting a combination of biomarkers namely APOE, Hcy, and SF in larger samples is required to support a clinical diagnosis of AD using a simple blood test.…”
Section: Predictor Value Of Plasma Thiols Blood Biomarkers and B-vitamin Status By Receiver Operating Characteristic Curvementioning
confidence: 99%
“…While folic acid and B12 possess antioxidant properties with the capacity to counteract such damage (16), the oxidative stress associated with AD pathology may also be due to Aβ-induced oxidative stress which increases plasma Hcy levels by depleting 5methyltetrahydrofolate (5-MTHF) (16). SF is also proposed as a useful biomarker of Aβ accumulation (18). Nevertheless, Hcy is a known independent risk factor for the development of AD, as is low serum folate (SF) (19).…”
The potential for B-vitamins to reduce plasma homocysteine (Hcy) and reduce the risk of Alzheimer's disease (AD) has been described previously. However, the role of Apolipoprotein E є4 (APOE4) in this relationship has not been adequately addressed. This case-control study explored APOE4 genotype in an Australian sample of 63 healthy individuals (female=38; age=76.9±4.7y) and 63 individuals with AD (female=35, age=77.1±5.3y). Findings revealed 55 of 126 participants expressed the APOE4 genotype, with 37 of 126 having both AD and the APOE4 genotype. Analysis revealed an increased likelihood of AD when Hcy levels are >11.0µmol/L (p=0.012), Cysteine levels were <255µmol/L (p=0.033) and Serum Folate was <22.0nmol/L (p=0.003; in males only). In females, dietary intake of total folate <336µg/day (p=0.001), natural folate <270µg/day (p=0.011) and vitamin B2 <1.12mg/day (p=0.028) was associated with an increased AD risk. These results support Hcy, Cys, and SF as useful biomarkers for AD, irrespective of APOE4 genotype and as such should be considered as part of screening and managing risk of AD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
