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Authors: Cavallaro, Rosaria A. | Fuso, Andrea | Nicolia, Vincenzina | Scarpa, Sigfrido

Article Type: Short Communication

Abstract: Oxidative stress, altered glutathione levels, and hyperhomocysteinemia play critical roles in Alzheimer's disease. We studied the relationships between hyperhomocysteinemia, glutathione, and oxidative stress in TgCRND8 mice maintained in conditions of folate, B12, and B6 deficiency and the effect of S-adenosylmethionine supplementation. We found that hyperhomocysteinemia was correlated with increased reduced/oxidized brain glutathione ratio, with decreased glutathione S-transferase activity and increased lipid peroxidation. S-adenosylmethionine potentiated superoxide dismutase and glutathione S-transferase activity and restored altered brain glutathione and erythrocytes lipid peroxidation. These results underline the importance of S-adenosylmethionine as neuroprotective compound, acting both on methylation and oxidation metabolism.

Keywords: Amyloid-β, glutathione, homocysteine, oxidative stress, S-adenosylmethionine

DOI: 10.3233/JAD-2010-091666

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 997-1002, 2010

Authors: Scarpa, Sigfrido | Cavallaro, Rosaria A. | D'Anselmi, Fabrizio | Fuso, Andrea

Article Type: Research Article

Abstract: Alzheimer disease (AD) is among the few diseases that may display high homocysteine (HCY) and low B12 and folate in blood. This observation has raised the suspect that amyloid-β overproduction and accumulation, which may be the cause of the disease, could be due to the loss of epigenetic control in the expression of the genes involved in AβPP (amyloid-β protein precursor) processing. We have shown, in cell culture, that two of the genes responsible for amyloid-β production are controlled by the methylation of their promoters. The process is strictly related to S-adenosylmethionine (SAM) metabolism. SAM is a natural compound, mainly …produced by the liver, which has been found at very low concentrations in AD brains. A further support to this thesis came from the observation that in elderly DNA methylations are consistently lower than in young and mid aged people. We are actually experimenting in transgenic mice the possibility to prevent or to arrest amyloid-β accumulation, through SAM administration, and therefore its significance and the use of this drug for the treatment of the disease. Show more

Keywords: Epigenomics, gene methylation, aging, Alzheimer disease, SAM, Homocysteine, SAH, B12, folate

DOI: 10.3233/JAD-2006-9406

Citation: Journal of Alzheimer's Disease, vol. 9, no. 4, pp. 407-414, 2006

Authors: Ricci, Serafino | Fuso, Andrea | Ippoliti, Flora | Businaro, Rita

Article Type: Review Article

Abstract: Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimer's disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development …and progression, as well as the possible ways of prevention, are discussed. Show more

Keywords: Alzheimer's disease, cytokines, HPA axis, lifestyle, neurogenesis, stress

DOI: 10.3233/JAD-2011-110821

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 11-24, 2012

Authors: Fuso, Andrea | Cavallaro, Rosaria A. | Zampelli, Alessandro | D'Anselmi, Fabrizio | Piscopo, Paola | Confaloni, Annamaria | Scarpa, Sigfrido

Article Type: Research Article

Abstract: Multiple aspects of homocysteine metabolism were studied to understand the mechanism responsible for hyperhomocysteinemia toxicity in Alzheimer disease. Besides oxidative stress and vascular damage, homocysteine has also a great importance in regulating DNA methylation through S-adenosylmethionine, the main methyl donor in eukaryotes. Alterations of S-adenosylmethionine and methylation were evidenced in Alzheimer disease and in elderly. In order to clarify whether DNA methylation can provide the basis for amyloid-β overproduction, we used human SK-N-BE neuroblastoma and A172 glioblastoma cell lines. We tested the effects of folate, B12 and B6 deprivation and S-adenosylmethionine addition on methylation metabolism. Our results indicate that homocysteine …accumulation induced through vitamin B deprivation could impair the “Methylation Potential” with consequent presenilin 1, BACE and amyloid-β upregulation. Moreover, we found that homocysteine alterations had an effect on neuroblastoma but not on glioblastoma cells; this suggests a possible differential role of the two cell types in Alzheimer disease. Show more

Keywords: S-adenosylmethionine, homocysteine, folate, vitamin B, DNA methylation, amyloid processing, presenilin 1

DOI: 10.3233/JAD-2007-11303

Citation: Journal of Alzheimer's Disease, vol. 11, no. 3, pp. 275-290, 2007

Authors: Cavallaro, Rosaria A. | Fuso, Andrea | D'Anselmi, Fabrizio | Seminara, Laura | Scarpa, Sigfrido

Article Type: Research Article

Abstract: High homocysteine (Hcy) together with low S-adenosylmethionine (SAM) levels are often observed in Alzheimer disease (AD), and this could be a sign of alteration of SAM/Hcy metabolism. It has already been shown that DNA methylation is involved in amyloid-β-protein precursor (AβPP) processing and amyloid-β(Aβ) production through the regulation of Presenilin 1 (PS1) expression and that exogenous SAM can silence the gene reducing Aβ. To investigate whether SAM administration globally influenced gene expression in the brain, we analysed 588 genes of the central nervous system in SK-N-BE neuroblastoma cells, with cDNA probes derived from untreated (DM; Differentiation Medium) or SAM treated …(DM+SAM) cultures. In these conditions only seven genes were modulated by SAM treatment (and therefore by DNA methylation); three were up-regulated and four down-regulated, showing low levels of modulation. Show more

Keywords: S-adenosylmethionine, homocysteine, DNA methylation, Alzheimer's disease, gene expression

DOI: 10.3233/JAD-2006-9407

Citation: Journal of Alzheimer's Disease, vol. 9, no. 4, pp. 415-419, 2006

Authors: Borro, Marina | Cavallaro, Rosaria A. | Gentile, Giovanna | Nicolia, Vincenzina | Fuso, Andrea | Simmaco, Maurizio | Scarpa, Sigfrido

Article Type: Research Article

Abstract: Late Onset Alzheimer's Disease (LOAD) can be associated to high homocysteine level and alteration of one-carbon metabolism. We previously demonstrated in the TgCRND8 mice strain, over-expressing human amyloid-β protein precursor, that B vitamin deficiency causes alteration of one-carbon metabolism, together with unbalance of S-adenosylmethionine/S-adenosylhomocysteine levels, and is associated with AD like hallmarks as increased amyloid-β plaque deposition, hyperhomocysteinemia, and oxidative stress. The same model of nutritional deficit was used here to study the variation of the brain protein expression profile associated to B vitamin deficiency. A group of proteins mainly involved in neuronal plasticity and mitochondrial functions was identified as …modulated by one-carbon metabolism. These findings are consistent with increasing data about the pivotal role of mitochondrial abnormalities in AD patho-physiology. The identified proteins might represent new potential biomarkers of LOAD to be further investigated. Show more

Keywords: Alzheimer's disease, homocysteine, proteomics, S-adenosylmethionine

DOI: 10.3233/JAD-2010-101107

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1257-1268, 2010

Authors: Nicolia, Vincenzina | Fuso, Andrea | Cavallaro, Rosaria A. | Di Luzio, Andrea | Scarpa, Sigfrido

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3β (GSK3β) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3β causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A …C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls ABα C heterotrimers formation. Here we demonstrate that GSK3β and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3β protein increase and a modulation in phosphorylation sites that regulate GSK3β activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3β and PP2A, leading to abnormal hyperphosphorylated tau. Show more

Keywords: B vitamin, homocysteine, GSK3β, PP2A, S-adenosylmethionine

DOI: 10.3233/JAD-2010-1284

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 895-907, 2010

Authors: Martire, Sara | Fuso, Andrea | Mosca, Luciana | Forte, Elena | Correani, Virginia | Fontana, Mario | Scarpa, Sigfrido | Maras, Bruno | d’Erme, Maria

Article Type: Research Article

Abstract: Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer’s disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer’s transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, …PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer’s disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism. Show more

Keywords: Alzheimer’s disease, bioenergetic metabolism, mitochondria, PARP-1, PKM2

DOI: 10.3233/JAD-151040

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 307-324, 2016

Authors: Milagre, Inês | Nunes, Maria João | Moutinho, Miguel | Rivera, Isabel | Fuso, Andrea | Scarpa, Sigfrido | Gama, Maria João | Rodrigues, Elsa

Article Type: Research Article

Abstract: The major mechanism of brain cholesterol elimination is the conversion of cholesterol into 24S-hydroxycholesterol by CYP46A1, a neuron-specific cytochrome P450. Since increasing evidence suggests that upregulation of CYP46A1 may be relevant for the treatment of Alzheimer's disease, we aim to identify the molecular mechanisms involved in CYP46A1 transcription. Our previous studies demonstrated the role of Sp transcription factors in basal expression and histone deacetylase (HDAC) inhibitor-dependent derepression of CYP46A1. Here, we show that the demethylating agent 5'-Aza-2'-deoxycytidine (DAC) is a CYP46A1 inducer and that pre-treatment with DAC causes a marked synergistic activation of CYP46A1 transcription by trichostatin A. Surprisingly, bisulfite …sequencing analysis revealed that the CYP46A1 core promoter is completely unmethylated in both human brain and non-neuronal human tissues where CYP46A1 is not expressed. Therefore, we have investigated Sp expression levels by western blot and real-time PCR, and their binding patterns to the CYP46A1 promoter, by electrophoretic mobility shift assay and chromatin immunoprecipitation assays, after DAC treatment. Our results showed that DAC decreases not only Sp1 and Sp3 protein levels, but also the binding activity of Sp3 to the +1 region of the CYP46A1 locus. Concomitantly, HDAC1 and HDAC2 were also significantly dissociated from the promoter. In conclusion, DAC induces CYP46A1 gene expression, in a DNA methylation-independent mechanism, decreasing Sp3/HDAC binding to the proximal promoter. Furthermore, by affecting the expression of the Sp3 transcription factor in neuronal cells, DAC might affect not only brain cholesterol metabolism, but also the expression of many other neuronal genes. Show more

Keywords: 5'-Aza-2'-deoxycytidine, brain cholesterol homeostasis, CYP46A1, 24S-hydroxycholesterol, epigenetics, Sp transcription factors, Trichostatin A

DOI: 10.3233/JAD-2010-100651

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1209-1221, 2010

Authors: Persichilli, Silvia | Gervasoni, Jacopo | Di Napoli, Alessandra | Fuso, Andrea | Nicolia, Vincenzina | Giardina, Bruno | Scarpa, Sigfrido | Desiderio, Claudia | Cavallaro, Rosaria A.

Article Type: Research Article

Abstract: Widely confirmed reports were published on association between hyperhomocysteinemia, B vitamin deficiency, oxidative stress, and amyloid-β in Alzheimer's disease (AD). Homocysteine, cysteine, cysteinylglycine and glutathione are metabolically interrelated thiols that may be potential indicators of health status and disease risk; they all participate in the metabolic pathway of homocysteine. Previous data obtained in one of our laboratories showed that B vitamin deficiency induced exacerbation of AD-like features in TgCRND8 AD mice; these effects were counteracted by S-adenosylmethionine (SAM) supplementation, through the modulation of DNA methylation and antioxidant pathways. Since the cellular response to oxidative stress typically involves alteration in thiols …content, a rapid and sensitive HPLC method with fluorescence detection was here used to evaluate the effect of SAM and superoxide-dismutase (SOD) supplementation on thiols level in plasma, in TgCRND8 mice. The quantitative data obtained from HPLC analysis of mice plasma samples showed significant decrease of thiols level when the B vitamin deficient diet was supplemented with SAM + SOD and SOD alone, the latter showing the greatest effect. All these considerations point out the measurement of plasma thiols concentration as a powerful tool of relevance for all clinical purposes involving the evaluation of oxidative stress. The coupling of HPLC with fluorimetric detection, here used, provided a strong method sensitivity allowing thiols determination at very low levels. Show more

Keywords: Alzheimer's disease, homocysteine, HPLC, S-adenosylmethionine, superoxide-dismutase, thiols

DOI: 10.3233/JAD-142391

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1323-1331, 2015