Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid ß plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

Imaging of trace elements in tissues: with a focus on laser ablation inductively coupled plasma mass spectrometry.

PURPOSE OF REVIEW: Elemental imaging techniques are capable of showing the spatial distribution of elements in a sample. Their application in biomedical sciences is promising, but they are not yet widely employed. The review gives a short overview about techniques available and then focuses on the advantages of using laser ablation inductively coupled plasma mass spectrometry for elemental bioimaging. Current examples for the use of elemental imaging with medical context are given to illustrate the potential of this type of analysis for clinical applications. RECENT FINDINGS: Recently, synchrotron-based techniques and laser ablation inductively coupled plasma mass spectrometry have been successfully applied to analyse the spatial distribution of elements in biological samples of medical relevance. SUMMARY: Elemental bioimaging methods have a great potential for medical applications. They are complementary to molecular imaging and histological staining and are especially attractive when used in combination with stable isotope tracer experiments.

Long-term zinc deprivation accelerates rat vascular smooth muscle cell proliferation involving the down-regulation of JNK1/2 expression in MAPK signaling.

BACKGROUND: The accelerated proliferation of vascular smooth muscle cells (VSMCs) is a contributor for atherosclerosis by thickening the vascular wall. Since zinc modulation of VSMC proliferation has not been clarified, this study investigated whether zinc affects VSMC proliferation. METHODS AND RESULTS: Both a rat aorta origin vascular smooth muscle cell line (A7r5 VSMCs) and primary VSMCs which were collected from rat aorta (pVSMCs) were cultured with zinc (0-50 µM Zn) for short- (≤12 d) and long-term (28 d) periods under normal non-calcifying (0 or 1 mM P) or calcifying (>2 mM P) P conditions. Mouse vascular endothelial cells (MS I cells) were also cultured (under 0-50 µM Zn and 10 mM P for 20 d) to compare with VSMC cultures. While during short-term culture of VSMCs, zinc deprivation decreased cell proliferation in a zinc-concentration manner both under non-calcifying and calcifying conditions in A7r5 and pVSMCs (P < 0.05), during long-term cultures (28 d), A7r5 VSMC proliferation was inversely related to medium zinc concentration under normal physiological P conditions (regression coefficient r(2) = -0.563, P = 0.012). The anti-cell proliferative effect of zinc supplementation (>50 µM) was VSMC-specific. Long-term (35 d), low zinc treatment down-regulated JNK expression and activation, while not affecting ERK1/2 MAPK signaling in A7r5 VSMCs. CONCLUSION: The results showed that chronic zinc deprivation accelerated VSMC proliferation, perhaps due to down-regulation of MAPK-JNK signaling, and that the anti-cell proliferative role of zinc is VSMC-specific. The findings suggested that zinc may have anti-VSMC proliferative properties in atherosclerosis.

Ginger phytochemicals mitigate the obesogenic effects of a high-fat diet in mice: a proteomic and biomarker network analysis.

SCOPE: Natural dietary anti-obesogenic phytochemicals may help combat the rising global incidence of obesity. We aimed to identify key hepatic pathways targeted by anti-obsogenic ginger phytochemicals fed to mice. METHODS AND RESULTS: Weaning mice were fed a high-fat diet containing 6-gingerol (HFG), zerumbone (HFZ), a characterized rhizome extract of the ginger-related plant Alpinia officinarum Hance (high fat goryankang, HFGK) or no phytochemicals (high-fat control, HFC) for 6 wks and were compared with mice on a low-fat control diet (LFC). Increased adiposity in the HFC group, compared with the LFC group, was significantly (p<0.05) reduced in the HFG and HFGK groups without food intake being affected. Correlation network analysis, including a novel residuals analysis, was utilized to investigate relationships between liver proteomic data, lipid and cholesterol biomarkers and physiological indicators of adiposity. 6-Gingerol significantly increased plasma cholesterol but hepatic farnesyl diphosphate synthetase, which is involved in cholesterol biosynthesis was decreased, possibly by negative feedback. Acetyl-coenzyme A acyltransferase 1 and enoyl CoA hydratase, which participate in the ß-oxidation of fatty acids were significantly (p<0.05) increased by consumption of phytochemical-supplemented diets. CONCLUSION: Dietary ginger phytochemicals target cholesterol metabolism and fatty acid oxidation in mice, with anti-obesogenic but also hypercholesterolemic consequences.

Zinc deprivation inhibits extracellular matrix calcification through decreased synthesis of matrix proteins in osteoblasts.

SCOPE: Zinc is implicated as an activator for bone formation, however, its influence on bone calcification has not been reported. This study examined how zinc regulates the bone matrix calcification in osteoblasts. METHODS AND RESULTS: Two osteoblastic MC3T3-E1 cell subclones (SC 4 and SC 24 as high and low osteogenic differentiation, respectively) were cultured in normal osteogenic (OSM), Zinc deficient (Zn-, 1 µM), or adequate (Zn+, 15 µM) media up to 20 days. Cells (SC 4) were also supplemented with (50 µg/mL) or no ascorbic acid (AA) in combination with Zinc treatment. Zn- decreased collagen synthesis and matrix accumulation. Although AA is essential for collagen formation, its supplementation could not compensate for Zinc deficiency-induced detrimental effects on extracellular matrix mineralization. Zn- also decreased the medium and cell layer alkaline phosphatase ALP activity. This decreased ALP activity might cause the decrease of Pi accumulation in response to Zn-, as measured by von Kossa staining. Ca deposition in cell layers, measured by Alizarin red S staining, was also decreased by Zn(-) . CONCLUSION: Our findings suggest that zinc deprivation inhibits extracellular matrix calcification in osteoblasts by decreasing the synthesis and activity of matrix proteins, type I collagen and ALP, and decreasing Ca and Pi accumulation. Therefore zinc deficiency can be considered as risk factor for poor extracellular matrix calcification.

Marginal zinc deficiency in rats decreases leptin expression independently of food intake and corticotrophin-releasing hormone in relation to food intake.

Zn deficiency reduces food intake and growth rate in rodents. To determine the relationship between Zn deficiency and the regulation of food intake, we evaluated leptin gene expression in epididymal white adipose tissue (eWAT), and hypothalamic corticotropin-releasing hormone (hCRH) and hypothalamic neuropeptide Y (hNPY) of rats Zn-deficient only to show reduced food intake and growth rate but not food intake cycling. Growing male Sprague-Dawley rats (240 g) were randomly assigned to one of four dietary groups: Zn-adequate (ZA; 30 mg/kg diet), Zn-deficient (ZD; 3 mg/kg diet), pair-fed with ZD (PF; 30 mg/kg diet) and Zn-sufficient (ZS; 50 mg/kg diet) (n 8), and were fed for 3 weeks. Food intake and body weight were measured, as were blood mononuclear cells and pancreas Zn levels. eWAT leptin, hCRH and hNPY mRNA levels were determined. Food intake was decreased by about 10 % in ZD and PF rats compared to ZA and ZS rats. Growth and eWAT leptin mRNA levels were unaffected in PF rats but were significantly (P < 0.05) decreased in ZD rats. However, hNPY showed a tendency to increase, and hCRH significantly (P < 0.05) decreased, in both ZD and PF rats. These results suggest that while leptin gene expression may be directly affected by Zn, hNPY and hCRH are likely responding to reduced food intake caused by Zn deficiency.

Leptin gene expression and serum leptin levels in zinc deficiency: implications for appetite regulation in rats.

Zinc deficiency in animals causes impaired growth and anorexia, and the mechanisms for these symptoms of zinc deficiency are not yet clear. We investigated whether circulating leptin levels and gene expression would be dysregulated under zinc deficiency and what would be the implications for appetite in rats. In study 1, 24 Sprague-Dawley rats were provided consecutively with three different dietary zinc intake levels: Zn-adequate (30 mg/kg of diet), Zn-depleted (1 mg/kg of diet), and Zn-replete (50 mg/kg of diet), for 1, 2, and 2 weeks, respectively. At the end of each dietary period, one-third of the rats were killed. In study 2, rats were assigned to one of the four Zn diet groups: Zn-adequate (30 mg/kg of diet), pair-fed (30 mg/kg of diet), Zn-deficient (1 mg/kg of diet), or Zn-sufficient (50 mg/kg of diet), and were fed for 4 weeks. Tissue Zn and serum leptin were measured, and leptin gene expression in adipose tissues (inguinal and abdominal) was determined by reverse transcription-polymerase chain reaction and northern blotting. Blood subfractions as plasma, red blood cells, and mononuclear cells and liver Zn level were decreased during the Zn-depletion period (P <.05). Serum leptin showed a tendency to increase during the Zn-depletion period and decreased back to the level of the Zn-repletion period. Leptin mRNA levels in inguinal adipocytes also increased during the Zn-depletion (P <.05) and Zn-deficient periods, which is consistent with the change in serum leptin. However, the decrease in leptin mRNA in abdominal adipocytes was not consistent with the increase in inguinal leptin levels and the change in serum leptin. Increased leptin levels in linguinal adipocytes is consistent with the expected physiological change of a decrease in appetite under Zn deficiency. However, before coming to any firm conclusion, further studies on adipose tissue-specific leptin expression, including the appetite-related neuropeptides, are necessary for clarifying the cause of lower appetite in zinc deficiency.