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

P4‐181: Homocysteine, S‐adenosylmethionine/s‐adenosylhomocysteine ratio, glutathione and nitric oxide levels in TgCRDND8 mice fed with B vitamin‐deficient diet

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HRV in active-duty special forces and public order military personnel

Heart rate variability (HRV) is a simple, non-invasive, real-time analyzable, and highly reproducible measurement that captures incidences for assessing a person’s health and physical condition. Public security jobs are characterized by major exposure to risk factors known to influence the cardiovascular response to stimuli, e.g., night shifts, highly physically demanding activity, and acute stress activity. This study aimed to evaluate the HRV parameters in a population of 112 male personnel of the special forces and public order of the Carabinieri, aged 25-59, when engaged in several duty tasks, such as paratroopers, night shift police station officers, night shift patrol, dynamic precision shooting evaluative team, dynamic precision shooting non-evaluative team, and office clerks (used as control group). During the specific task of each participant, the HRV parameters were collected with wearable devices and processed. The HRV parameters in the time and frequency domains collected were average heart rate, standard deviation of all normal RR intervals, root mean square of successive differences in adjacent normal-to-normal (NN) intervals, very-low-frequency power, low-frequency power, high-frequency power, stress index, parasympathetic nervous system activity index, and sympathetic nervous system activity index. Parametric tests for independent series to compare the HRV parameters by subgroups within the study subjects were used. A multivariate linear regression analysis was conducted to evaluate the association between the HRV parameters and some personal and organizational factors. The comparison between different subgroups showed that activities with a high demand for concentration and precision, as is the case with paratroopers and dynamic precision shooters, differ significantly from activities that can be defined as routine, such as office work. Other activities, such as patrolling or remote management from operations centers, although including critical elements, did not deviate significantly from the control group. The study of HRV parameters is therefore a useful tool for occupational physicians, both for addressing work suitability assessments and for better targeting health promotion campaigns, to be considered as being aimed at monitoring the subject’s physiological parameters, and not at the diagnosis of any pathological condition, which should always be carried out by the medical specialist

S-Adenosylmethionine Prevents Oxidative Stress and Modulates Glutathione Metabolism in TgCRND8 Mice Fed a B-Vitamin Deficient Diet

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

B Vitamin Deficiency Promotes Tau Phosphorylation Through Regulation of GSK3 beta and PP2A

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 3beta (GSK3beta) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3beta 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 AB_{alpha}C heterotrimers formation. Here we demonstrate that GSK3beta 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 GSK3beta protein increase and a modulation in phosphorylation sites that regulate GSK3beta activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3beta and PP2A, leading to abnormal hyperphosphorylated tau

IS RAGE THE SO FAR UNIDENTIFIED TRAIT D'UNION BETWEEN VASCULAR RISK FACTORS AND ALZHEIMER'S DISEASE?

889 IS RAGE THE SO FAR UNIDENTIFIED TRAIT D'UNION BETWEEN VASCULAR RISK FACTORS AND ALZHEIMER'S DISEASE? Rita Businaro1, L. Capriotti1, M. Corsi1, M. Leopizzi1, V. Nicolia2, A. Fuso2 1Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, 2Surgery 'P. Valdoni', Sapienza University of Rome, Rome, Italy Aim: The receptor for advanced glycation end products (RAGE), is considered to be a key mediator of atherogenesis. Recent findings indicate the important role played by RAGE in the progression of Alzheimer's disease (AD). It has been shown that RAGE signaling contributes to the production of proinflammatory cytokines, leading to the impairment of neuronal functions and to the amyloid accumulation. Moreover, atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction and trigger AD pathology. It is known that diet depleted in folate and vitamins B6 and B12 promotes an enhanced expression of RAGE and leads to hyperhomocysteinemia, a well-known risk factor for the development of cardiovascular disease as well as for late onset AD. This work aims at evaluating the effects of hyperhomocysteinemia, induced by B vitamin deficiency, on RAGE expression. Methods: TgCNRD8 mice carrying a Indiana/Swedish mutated APP transgene, an animal model of AD, were grown either with control or B vitamin deficient diet. We measured RAGE by immunohistochemistry, western blots, real-time PCR. Results: B vitamin deficiency enhances RAGE expression in particular at the level of frontal and parietal microvasculature. Both neurons and endothelium in the hippocampus were stained, showing an increase in the number of positive cells as well as in the amount of reaction, compared to the animals fed with a standard diet. Conclusions: B vitamin deficiency and hyperomocysteinemia are able to modulate RAGE expression, promoting in this way atherosclerosis progression and the transport of beta Amyloid across the BBB