Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, there is increasing evidence that the previously so-called "secondary factors" such as a disturbed glucose metabolism, oxidative stress and formation of "advanced glycation endproducts" (AGEs) and their interaction in a vicious cycle are also important for the onset and progression of AD. AGEs are protein modifications that contribute to the formation of the histopathological and biochemical hallmarks of AD: amyloid plaques, neurofibrillary tangles and activated microglia. Oxidative modifications are formed by a complex cascade of dehydration, oxidation and cyclisation reactions, subsequent to a non-enzymatic reaction of sugars with amino groups of proteins. Accumulation of AGE-crosslinked proteins throughout life is a general phenomenon of ageing. However, AGEs are more than just markers of ageing since they can also exert adverse biologic effects on tissues and cells, including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress). Oxidative stress is involved in various divergent events leading to cell damage, including an increase in membrane rigidity, DNA strand breaks and an impairment in glucose uptake. In addition, other age-related metabolic changes such as depletion of antioxidants or decreased energy production by a disturbed glucose metabolism diminish the ability of the cell to cope with the effects of radical-induced membrane, protein and DNA damage. With our improving understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the elucidation of the etiologic causes, particularly the positive feedback loops involving radical damage and a reduced glucose metabolism, will help to develop novel "neuroprotective" treatment strategies able to interrupt this vicious cycle of oxidative stress and energy shortage in AD.
Advanced glycation endproducts (AGEs) accumulate on long-lived protein deposits including beta-amyloid plaques in Alzheimer's disease (AD). AGE-modified amyloid deposits contain oxidized and nitrated proteins as markers of a chronic neuroinflammatory condition and are surrounded by activated microglial and astroglial cells. We show in this study that AGEs increase nitric oxide production by induction of the inducible nitric oxide synthase (iNOS) on the mRNA and protein level in the murine microglial cell line N-11. Membrane permeable antioxidants including oestrogen derivatives (e.g. 17beta-oestradiol) thiol antioxidants (e.g. (R+)-alpha-lipoic acid) and Gingko biloba extract EGb 761, but not phosphodiesterase inhibitors such as propentophylline, prevent the up-regulation of AGE-induced iNOS expression and NO production. These results indicate that oxygen free radicals serve as second messengers in AGE-induced pro-inflammatory signal transduction pathways. As this pharmacological mechanism is not only relevant for Alzheimer's disease, but also for many chronic inflammatory conditions, such membrane-permeable antioxidants could be regarded not only as antioxidant, but also as potent therapeutic anti-inflammatory drugs.
Oxidative stress is believed to play a decisive role in the pathogenesis of Parkinson's disease (PD). In addition, Lewy bodies, densely crosslinked intracellular protein deposits formed from cytoskeletal components, accumulate in presymptomatic stages of the disease. Recent findings indicate that "advanced glycation end products" (AGEs) are the major structural crosslinkers that cause the transformation of soluble neurofilament proteins to insoluble Lewy bodies. AGE formation is increased under conditions of oxidative stress, such as early GSH depletion, that are evident in the substantia nigra of PD patients, and is inhibited by radical scavengers and thiol antioxidants. Because AGEs not only are markers of oxidative stress but are also active participants in cell signaling by activation of glial cells to produce superoxide and nitric oxide, they can be considered part of a vicious cycle, which finally leads to neuronal cell death in the substantia nigra in PD.Münch G, Gerlach M, Sian J, Wong A, Riederer P. Advanced glycation end products in neurodegeneration: more than early markers of oxidative stress? Ann Neurol 1998;44(Suppl 1):S85-S88
As professional phagocytes, macrophages are susceptible to endolysosomal membrane damage inflicted by the pathogens and noxious particles they ingest. Whether macrophages have mechanisms for limiting such damage is not well understood. Previously, we reported a phenomenon, termed “inducible renitence,” in which lipopolysaccharide (LPS) activation of macrophages protected their endolysosomes against damage initiated by the phagocytosis of silica beads. To gain mechanistic insight into the process, we analyzed the kinetics of renitence and morphological features of LPS-activated versus resting macrophages following silica bead–mediated injury. We discovered novel vacuolar structures that form in LPS-activated but not resting macrophages following silica bead phagocytosis. Because of their correlation with renitence and damage-resistant nature, we termed these structures “renitence vacuoles” (RVs). RVs formed coincident with silica bead uptake in a process associated with membrane ruffling and macropinocytosis. However, unlike normal macropinosomes (MPs), which shrink within 20 min of formation, RVs persisted around bead-containing phagosomes. RVs fused with lysosomes, whereas associated phagosomes typically did not. These findings are consistent with a model in which RVs, as persistent MPs, prevent fusion between damaged phagosomes and intact lysosomes and thereby preserve endolysosomal integrity.
Severe acquired aplastic anemia (AA) is a fatal disorder characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Evidence in most AA patients indicates that IFN-g-producing T helper (Th)1 effector CD4+ T cells are important for mediating bone marrow (BM) failure in AA. However, the efficacy of standard therapies that typically include antithymocyte globulin and cyclosporine A is limited, and novel approaches are urgently needed. Ezh2 is a histone methyltransferase that specifically catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3) and acts primarily as a gene silencer. We investigated whether Ezh2 regulatory control governs Th1 immune-mediated cytopenias in AA. We tested this hypothesis in a mouse model of AA using genetic approaches of Ezh2 inhibition. In naïve CD4+ T cells, high levels of H3K27me3 are correlated with repressed expression of IFNG and TBX21, the gene that encodes T-bet, which is essential for inducing IFN-g expression. Upon Th1 cell differentiation, the regulatory regions of both IFNG and TBX21 gene loci show a marked reduction of H3K27me3. We found that Ezh2 is required to induce Th1 cell differentiation and T cell-mediated AA in mice. Conditionally deleting Ezh2 in mature T cells had the effect of dramatically reducing the production of Th1 cells secreting high levels of IFN-g in vivo, decreasing BM-infiltrating Th1 cells during active disease, and rescuing mice from BM failure. In vitro culture assays confirmed that Ezh2-deficient T cells showed significantly reduced production of IFN-g under Th1-skewing conditions compared to wild-type (WT) T cells. This effect of Ezh2 deficiency on Th1 cell differentiation was accompanied by a marked decrease in the expression of both IFNG and TBX21 genes. These results stand in sharp contrast to the conventional view that Ezh2 and its catalyzed H3K27me3 may repress gene expression, and the corollary that loss of Ezh2 may result in increased production of IFN-g and T-bet. Using chromatin immunoprecipitation assay, we found that upon Th1 cell differentiation in vitro, naïve WT CD4+ T cells showed a significant reduction of H3K27me3 at the regulatory region of both IFNG and TBX21 gene loci, in agreement with previous reports. In contrast, high levels of Ezh2 were detected at the regulatory region of the TBX21 gene in activated WT CD4+ T cells, suggesting that Ezh2 may be required to promote TBX21 transcription during Th1 cell development. To test this possibility, we infected Ezh2-deficient CD4+ T cells with a retrovirus construct encoding T-bet. Ectopic expression of T-bet rescued Th1 cell differentiation of Ezh2-deficient T cells in vitro. Collectively, our findings identify a critical role for Ezh2 in regulating Th1 responses and AA. Given the availability of Ezh2-specific inhibitors newly developed for cancer therapy in clinical trials, we propose that targeting Ezh2 should be investigated as a new strategy for treating AA in patients. Disclosures: No relevant conflicts of interest to declare.
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