Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc

Abeta binds Zn(2+), Cu(2+), and Fe(3+) in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn(2+) precipitates Abeta in vitro, and Cu(2+) interaction with Abeta promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H(2)O(2) (Abeta1-42 > Abeta1-40 > ratAbeta1-40). Because Zn(2+) is redox-inert, we studied the possibility that it may play an inhibitory role in H(2)O(2)-mediated Abeta toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu(2+), Zn(2+) rescued primary cortical and human embryonic kidney 293 cells that were exposed to Abeta1-42, correlating with the effect of Zn(2+) in suppressing Cu(2+)-dependent H(2)O(2) formation from Abeta1-42. Since plaques contain exceptionally high concentrations of Zn(2+), we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn(2+) in AD, where plaques form as the result of a more robust Zn(2+) antioxidant response to the underlying oxidative attack.     

Cellular Zinc Levels Are Modulated by TRPML1–TMEM163 Interaction

Mucolipidosis type IV (MLIV) is caused by loss of function mutations in the TRPML1 ion channel. We previously reported that tissue zinc levels in MLIV were abnormally elevated; however, the mechanism behind this pathologic accumulation remains unknown. Here, we identify transmembrane (TMEM)‐163 protein, a putative zinc transporter, as a novel interacting partner for TRPML1. Evidence from yeast two‐hybrid, tissue expression pattern, co‐immunoprecipitation, mass spectrometry and confocal microscopy studies confirmed the physical association of TMEM163 with TRPML1. This interaction is disrupted when a part of TMEM163's N‐terminus was deleted. Further studies to define the relevance of their interaction revealed that the plasma membrane (PM) levels of TMEM163 significantly decrease when TRPML1 is co‐expressed in HEK‐293 cells, while it mostly localizes within the PM when co‐expressed with a mutant TRPML1 that distributes mostly in the PM. Meanwhile, co‐expression of TMEM163 does not alter TRPML1 channel activity, but its expression levels in MLIV patient fibroblasts are reduced, which correlate with marked accumulation of zinc in lysosomes when these cells are acutely exposed to exogenous zinc (100 μM). When TMEM163 is knocked down or when TMEM163 and TRPML1 are co‐knocked down in HEK‐293 cells treated overnight with 100 nm zinc, the cells have significantly higher intracellular zinc levels than untreated control. Overall, these findings suggest that TMEM163 and TRPML1 proteins play a critical role in cellular zinc homeostasis, and thus possibly explain a novel mechanism for the pathological overload of zinc in MLIV disease.      

Analysis of silver binding nucleolar organizer regions in exfoliative cytology smears of potentially malignant and malignant oral lesions

Nucleolar organizer regions are nucleolar components that contain proteins that are stained selectively by silver methods; they can be identified as black dots throughout the nucleolus and are known as silver binding nucleolar organizer regions (AgNOR). The number of AgNOR is related to the cell cycle and the proliferative activity of the cells. We investigated AgNOR using exfoliative cytology smears of potentially malignant oral lesions. Eighty individuals were divided into four equal groups: healthy controls, oral leukoplakia, oral submucous fibrosis and oral squamous cell carcinoma. The mean number of AgNOR in each study group gradually increased from control to oral leukoplakia to oral submucous fibrosis to oral squamous cell carcinoma. The proliferative index was increased in the oral premalignant and malignant patients compared to normal subjects. The mean AgNOR size gradually increased from control to oral leukoplakia to oral submucous fibrosis to oral squamous cell carcinoma. Spherical shaped AgNOR were most common in controls, whereas large, clustered and kidney shapes were most common in oral squamous cell carcinoma. Multiparameter analysis of AgNOR in oral exfoliative smears is a simple, sensitive and cost-effective method for differentiating premalignant from malignant lesions and can be used in conjunction with routine cytomorphological evaluation.     

DELAYED URIC ACID ACCUMULATION IN PLASMA PROVIDES ADDITIONAL ANTI-OXIDANT PROTECTION AGAINST IRON-TRIGGERED OXIDATIVE STRESS AFTER A WINGATE TEST

Reactive oxygen species are produced during anaerobic exercise mostly by Fe ions released into plasma and endothelial/muscle xanthine oxidase activation that generates uric acid (UA) as the endpoint metabolite. Paradoxically, UA is considered a major antioxidant by virtue of being able to chelate pro-oxidative iron ions. This work aimed to evaluate the relationship between UA and plasma markers of oxidative stress following the exhaustive Wingate test. Plasma samples of 17 male undergraduate students were collected before, 5 and 60 min after maximal anaerobic effort for the measurement of total iron, haem iron, UA, ferric-reducing antioxidant activity in plasma (FRAP), and malondialdehyde (MDA, biomarker of lipoperoxidation). Iron and FRAP showed similar kinetics in plasma, demonstrating an adequate pro-/antioxidant balance immediately after exercise and during the recovery period (5–60 min). Slight variations of haem iron concentrations did not support a relevant contribution of rhabdomyolysis or haemolysis for iron overload following exercise. UA concentration did not vary immediately after exercise but rather increased 29% during the recovery period. Unaltered MDA levels were concomitantly measured. We propose that delayed UA accumulation in plasma is an auxiliary antioxidant response to post-exercise (iron-mediated) oxidative stress, and the high correlation between total UA and FRAP in plasma (R-Square = 0.636; p = 0.00582) supports this hypothesis.     

The attitudes of riparian communities to the presence of water hyacinth in the Wouri River Basin,Douala, Cameroon

Since publication of the first record of Eichhornia crassipes in Cameroon in 1997, the weed has become highly invasive in the Wouri River Basin. Between June and September 2014, a socio-economic survey using participatory and qualitative methods was undertaken in the riparian villages of the Wouri River Basin to assess the perception of respondents to the presence of water hyacinth. The survey revealed that water hyacinth was a significant threat to activities along the river, which included fishing, sand extraction and river transportation. The presence of water hyacinth mats reduced catch rates of several common fish species, river transportation by 75%, and significantly reduced the income for sand extraction. Cameroon employs manual clearing of water hyacinth; however, respondents indicated they would consider other control methods, provided they do not have any negative impacts.