It is well known NK cells play a role in immune surveil lance for cancer and tha

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It is well known NK cells play a role in immune surveil lance for cancer and tha

Mensagem  jy9202 em Qui Maio 15, 2014 1:25 am

SNOC and H2O2 have opposing effects on BACE1 enzymatic activity and subsequent Ab generation Since S nitrosylation occurs at critical Cys residues which often leads to alteration of the structure and function of the target proteins, we examined BACE1 enzymatic activity upon SNOC and H2O2 treatments. Interestingly, SNOC BACE1 shows reduced enzymatic ABT-888 Veliparib activity while oxidized BACE1 exhibits enhanced activ ity, assays were performed with a commercial kit using both cell lysates and purified recombinant protein. Accordingly, SNOC and H2O2 display oppo site effects on Ab generation, as determined by IP Westerns using an antibody specific to Ab. Consistent with the dose dependent effects of H2O2 on BACE1 transcription, H2O2 also shows an effect dependent on the same dosages that induce BACE1 and Ab generation, with a maximum effect seen at 10 uM.<br><br> SNO BACE1 levels decrease in late stage AD brains which inversely correlates with BACE1 protein levels We next investigated whether S nitrosylation of BACE1 occurred in vivo in neurodegenerative disorders asso AEB071 ic50 ciated with high levels of nitrosative stress, such as stroke and AD. We included in our tests those speci mens taken from autopsy patients diagnosed at an early stage of AD called mild cognitive impairment and compared them to age matched control brain speci mens. We chose to examine the entorhinal cortices, the most vulnerable region in AD brains. The patient cohort and information are summarized in the additional table. From semi quantitative profiling of SNO BACE1 and total BACE1 in 18 human brains, we found that SNO BACE1 was at high levels in control and MCI samples and was markedly reduced in the late stage AD brains.<br><br> Discussion It is widely accepted that oxidative stress is one of the earliest changes that occurs in the pathogenesis of AD, arising from the imbalance between increased produc tion of reactive oxygen and nitrogen AG-1478 Tyrphostin AG-1478 species and impaired antioxidant defenses, as reflected in the accumulation of oxidative damage to macromolecules detected in MCI and AD brains. In this work, we present in vitro and in vivo evidence of NO mediated regulation of BACE1. We are the first to demonstrate that NO, at different levels, can exert dif ferential regulation on BACE1, at low levels, NO sup presses BACE1 transcription while at modest to high levels, NO induces S nitrosylation of BACE1 and inacti vates the enzyme.<br><br> Furthermore, we show that S nitrosy lation of BACE1 occurs in normal aging and MCI brains but is significantly diminished in late stage AD brains. Given the central role of Ab in AD pathogenesis and the fact that BACE1 is the rate limiting enzyme in APP processing and Ab generation, the redox regulation of BACE1 identified herein may represent a novel and crucial mechanism for keeping BACE1 at physiological levels activity. The multifaceted actions of the NO group can be clas sified into two categories, classic NO mediated cGMP dependent actions and reactive nitrogen species mediated cGMP independent actions. The cGMP depen dent actions often play critical roles in a variety of phy siological processes, including NO mediated vasodilation.


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