Nutrition-Based Modulation of Poly-ADP-Ribosylation and its possible role in Alzheimer’s disease

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and the main reason of dementia in the elderly. On the pathological point of view, it is characterized by extracellular aggregates of amyloid peptides and intracellular deposits of tau protein. These deposits affect neuron viability and functions by inducing (among other pathological pathways) oxidative stress and triggering mitochondrial dysfunction. It is now evident that free radicalinduced oxidative damage is strongly involved in the pathogenesis of AD. Oxidative damage occurs early in disease pathogenesis and can exacerbate its progression. Post-mortem brain of individuals affected by AD, evidenced an extensive state of oxidative stress compared to healthy controls; markers of increased oxidation include, among others, DNA damage. DNA damage can induce the activity of the enzyme poly (ADP-ribose) polymerase 1 (PARP-1) that catalyze the reaction of poly (ADP-ribosylation). This post-translational modification modulates the functions of proteins involved in many physiological processes such as gene expression, maintenance of genomic stability and cell death. Therefore, inhibiting PARP-1 activity can represent a possible new strategy to reduce the impact of the oxidative stress in AD as well as in other neurodegenerative diseases. Here we discuss the role of nutrients in modulating PARP-1 activity and its perspective potential application

Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation

S-adenosylmethionine and superoxide dismutase 1 synergistically counteract Alzheimer's disease features progression in tgCRND8 mice

Recent evidence emphasizes the role of dysregulated one-carbon metabolism in Alzheimer's Disease (AD). Exploiting a nutritional B-vitamin deficiency paradigm, we have previously shown that PSEN1 and BACE1 activity is modulated by one-carbon metabolism, leading to increased amyloid production. We have also demonstrated that S-adenosylmethionine (SAM) supplementation contrasted the AD-like features, induced by B-vitamin deficiency. In the present study, we expanded these observations by investigating the effects of SAM and SOD (Superoxide dismutase) association. TgCRND8 AD mice were fed either with a control or B-vitamin deficient diet, with or without oral supplementation of SAM + SOD. We measured oxidative stress by lipid peroxidation assay, PSEN1 and BACE1 expression by Real-Time Polymerase Chain Reaction (PCR), amyloid deposition by ELISA assays and immunohistochemistry. We found that SAM + SOD supplementation prevents the exacerbation of AD-like features induced by B vitamin deficiency, showing synergistic effects compared to either SAM or SOD alone. SAM + SOD supplementation also contrasts the amyloid deposition typically observed in TgCRND8 mice. Although the mechanisms underlying the beneficial effect of exogenous SOD remain to be elucidated, our findings identify that the combination of SAM + SOD could be carefully considered as co-adjuvant of current AD therapies

The conformational evolution of elongated polymer solutions tailors the polarization of light-emission from organic nanofibers

Polymer fibers are currently exploited in tremendously important technologies. Their innovative properties are mainly determined by the behavior of the polymer macromolecules under the elongation induced by external mechanical or electrostatic forces, characterizing the fiber drawing process. Although enhanced physical properties were observed in polymer fibers produced under strong stretching conditions, studies of the process-induced nanoscale organization of the polymer molecules are not available, and most of fiber properties are still obtained on an empirical basis. Here we reveal the orientational properties of semiflexible polymers in electrospun nanofibers, which allow the polarization properties of active fibers to be finely controlled. Modeling and simulations of the conformational evolution of the polymer chains during electrostatic elongation of semidilute solutions demonstrate that the molecules stretch almost fully within less than 1 mm from jet start, increasing polymer axial orientation at the jet center. The nanoscale mapping of the local dichroism of individual fibers by polarized near-field optical microscopy unveils for the first time the presence of an internal spatial variation of the molecular order, namely the presence of a core with axially aligned molecules and a sheath with almost radially oriented molecules. These results allow important and specific fiber properties to be manipulated and tailored, as here demonstrated for the polarization of emitted light.Comment: 45 pages, 10 figures, Macromolecules (2014

Involvement of sperm acetylated histones and the nuclear isoform of Glutathione peroxidase 4 in fertilization

We previously demonstrated that the nuclear form of Glutathione peroxidase 4 (nGPx4) has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome and that sperm lacking nGPx4 are more prone to decondensation in vitro. In this study we have hypothesized that sperm retained acetylated histones and nGPx4 are implicated in paternal chromatin decondensation and male pronucleus formation at fertilization. Indeed, significant higher amounts of acetylated histone H4 and acetylated histone H3 were observed by both immunofluorescence and western blotting in nGPx4-KO sperm vs WT ones. In vitro fertilization of zona pellucida- deprived oocytes by WT sperm in the presence of trichostatin (TSA) also demonstrated that paternal histone acetylation was inversely related to the timing of sperm nucleus decondensation at fertilization. In contrast, TSA had no effect on nGPx4-KO sperm, indicating they had a maximal level of histone acetylation. Moreover the paternally imprinted gene Igf2/H19 was hypomethylated in KO sperm compared to WT ones. The lack of nGPx4 negatively affected male fertility, causing a marked decrease in total pups and pregnancies with delivery, a significant reduction in pronuclei (PN) embryos in in vitro fertilization assays and an approximately 2 h delay in egg fertilization in vivo. Because the zona pellucida binding and fusion to oolemma of nGPx4-KO and WT sperm were similar, the subfertility of nGPx4 sperm reflected a decreased sperm progression through egg cumulus/zona pellucida, pinpointing a defective acrosome in line with acrosomal nGPx4 localization. We conclude that paternal acetylated histones and acrosomal nGPx4 are directly involved in fertilization

Alzheimer's Disease Promotion by Obesity: Induced Mechanisms—Molecular Links and Perspectives

The incidence of AD is increasing in parallel with the increase in life expectancy. At the same time the prevalence of metabolic syndrome and obesity is reaching epidemic proportions in western populations. Stress is one of the major inducers of visceral fat and obesity development, underlying accelerated aging processes. Adipose tissue is at present considered as an active endocrine organ, producing important mediators involved in metabolism regulation as well as in inflammatory mechanisms. Insulin and leptin resistance has been related to the dysregulation of energy balance and to the induction of a chronic inflammatory status which have been recognized as important cofactors in cognitive impairment and AD initiation and progression. The aim of this paper is to disclose the correlation between the onset and progression of AD and the stress-induced changes in lifestyle, leading to overnutrition and reduced physical activity, ending with metabolic syndrome and obesity. The involved molecular mechanisms will be briefly discussed, and advisable guide lines for the prevention of AD through lifestyle modifications will be proposed

Aggregation-Induced Emission of Tetraphenylethylene in Styrene-Based Polymers

In the present work, the preparation of different styrene-based polymer films containing small amounts of TPE and the evaluation of their photoluminescent behaviour is reported. When TPE is dispersed in a poor solvent or in a glassy PS matrix, the arrested intramolecular rotations of its aryls favour the strong emission of light centred at about 455-460 nm. Conversely, TPE fluorescence significantly weakens to a faint signal when good solvents or viscous but not glassy polymer matrices are used. Near-field optical microscopy correlates the fluorescence behaviour with the different matrix morphologies. These results should be able to be used for developing a new tool for polymer traceability

Perinatal S-Adenosylmethionine Supplementation Represses PSEN1 Expression by the Cellular Epigenetic Memory of CpG and Non-CpG Methylation in Adult TgCRD8 Mice

DNA methylation, the main epigenetic modification regulating gene expression, plays a role in the pathophysiology of neurodegeneration. Previous evidence indicates that 50 -flanking hypomethylation of PSEN1, a gene involved in the amyloidogenic pathway in Alzheimer’s dis- ease (AD), boosts the AD-like phenotype in transgenic TgCRND8 mice. Supplementation with S-adenosylmethionine (SAM), the methyl donor in the DNA methylation reactions, reverts the patho- logical phenotype. Several studies indicate that epigenetic signatures, driving the shift between normal and diseased aging, can be acquired during the first stages of life, even in utero, and manifest phenotypically later on in life. Therefore, we decided to test whether SAM supplementation during the perinatal period (i.e., supplementing the mothers from mating to weaning) could exert a protec- tive role towards AD-like symptom manifestation. We therefore compared the effect of post-weaning vs. perinatal SAM treatment in TgCRND8 mice by assessing PSEN1 methylation and expression and the development of amyloid plaques. We found that short-term perinatal supplementation was as effective as the longer post-weaning supplementation in repressing PSEN1 expression and amyloid deposition in adult mice. These results highlight the importance of epigenetic memory and methyl donor availability during early life to promote healthy aging and stress the functional role of non-CpG methylation

Blending or Bonding? Mechanochromism of an Aggregachromic Mechanophore in a Thermoplastic Elastomer

A straightforward way for the preparation of mechanochromic polymers consists of incorporating a suitable content of a mechanophore in the polymeric matrix either by physical dispersion or via covalent functionalization. Although covalent incorporation may require demanding chemical efforts, this approach can offer significant advantages over physical dispersion. In this work, a common thermoplastic elastomer, styrene-b-(ethylene-co-butylene)-b-styrene triblock copolymer grafted with maleic anhydride (SEBS-MAH), was covalently functionalized with 1-aminomethylpyrene (AMP). MAH functional groups are covalently linked to the ethylene-co-butylene blocks, thus allowing a precise and selective confinement of the chromogenic AMP units in the soft block. Flat, fully conjugated pyrene units undergo the reversible formation of π-πaggregates, readily distinguishable by their red-shifted emission. These aggregates were heavily affected by the application of mechanical stimuli. Despite the low degree of mechanophore functionalization (about 1 wt %), uniaxial deformation of the polymer was reliably monitored via fluorescence and a clear drop in the excimer to monomer emission ratio (IE/IM) was observed starting from 50% of strain. The marked mechanochromism was confirmed by emission lifetime measurements and also by near-field investigations. In addition, the mechanoresponse showed good reversibility after repeated stress-relaxation cycles. Control experiments performed on formulations comprising a physical dispersion of pyrene in unfunctionalized SEBS showed faint excimer emission and a negligible mechanochromic response up to 5 wt % of doping, in substantial agreement with the scanning near-field optical microscopy analysis. An evident drop of the IE/IM ratio occurred for 10 wt % of pyrene, albeit the excimer emission remained predominant even at the highest deformation, being a smaller fraction of pyrene moieties involved. Overall, the covalent approach appeared as an elegant procedure to confine the chromogenic unit in the soft phase of block copolymers and thus to provide an elastomeric film showing a detectable and reversible mechanochromic response with a modest (i.e., ∼1 wt %) amount of pyrene molecules, i.e., 10 times smaller compared to the dispersed system

Printed Electrochemical Strip for the Detection of miRNA-29a: A Possible Biomarker Related to Alzheimer's Disease

The development of electrochemical strips, as extremely powerful diagnostic tools, has received much attention in the field of sensor analysis and, in particular, the detection of nucleic acids in complex matrixes is a hot topic in the electroanalytical area, especially when directed toward the development of emerging technologies, for the purpose of facilitating personal healthcare. One of the major diseases for which early diagnosis is crucial is represented by Alzheimer's disease (AD). AD is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. In this context microRNAs (miRNAs), which are small noncoding RNAs, have recently been highlighted for their promising role as biomarkers for early diagnosis. In particular, miRNA-29 represents a class of miRNAs known to regulate pathogenesis of AD. In this work we developed an electrochemical printed strip for the detection of miRNA-29a at low levels. The architecture was characterized by the presence of gold nanoparticles (AuNPs) and an anti-miRNA-29a probe labeled with a redox mediator. The novel analytical tool has been characterized with microscale thermophoresis and electrochemical methods, and it has been optimized by selection of the most appropriate probe density to detect low target concentration. The present tool was capable to detect miRNA-29a both in standard solution and in serum, respectively, down to 0.15 and 0.2 nM. The platform highlighted good repeatability (calculated as the relative standard deviation) of ca. 10% and satisfactory selectivity in the presence of interfering species. This work has the objective to open a way for the study and possible early diagnosis of a physically and socially devastating disease such as Alzheimer's. The results demonstrate the suitability of this approach in terms of ease of use, time of production, sensitivity, and applicability