Aluminum modulates effects of beta amyloid(1-42) on neuronal calcium homeostasis and mitochondria functioning and is altered in a triple transgenic mouse model of Alzheimer's disease.

Recent findings suggest that beta-amyloid (A beta) is more neurotoxic when present in its oligomeric configuration rather than as monomers or fibrils. Previous work from our laboratories has shown that A beta aggregation is strongly influenced by the conjugation of the peptide with metal ions (aluminum A, copper [Cu], zinc [Zn], and iron [Fe]) that are found in high concentrations in the core of senile plaques. Disruption of Ca++ signaling and mitochondrial dysfunction are potent triggers of neuronal death and have been implicated in the neuronal loss that is associated with Alzheimer's disease (AD). In this study, we explored whether A beta-metal complexes can have detrimental effects on intraneuronal Ca++ ([Ca++]i) homeostasis and mitochondrial function in vitro. Results from our experiments indicate that, when conjugated with Al, A beta perturbs neuronal [Ca++]i homeostasis and inhibits mitochondrial respiration. Finally, we analyzed the content of the four metals in the brain of a triple transgenic animal model of AD and found that Al is the only one to be increased in the cortex of these mice.

Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is responsible for the most common form of dementia among elderly people. Signature features of the AD brain are intra/extracellular deposits of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau. Recent evidence indicates that in AD altered Zn(2+) homeostasis can play an important role in the development of the disease as the cation promotes Abeta oligomerization and plaque formation. In this study, we investigated whether intraneuronal Zn(2+) homeostasis is affected by known "pro-AD factors" such as mutant forms of the amyloid precursor (APP), presenilin-1 (PS1), and tau proteins. Oxidative stress is a potent trigger for mobilization of intracellular free Zn(2+) ([Zn(2+)](i)) and we therefore evaluated ROS-driven [Zn(2+)](i) rises in neurons obtained from triple transgenic AD mice (3xTg-AD) that express mutant APP, PS1 and tau. In this study, [Zn(2+)](i) rises triggered by prolonged exposure to the membrane-permeant oxidizing agent 2,2'-dithiodipyridine were found to be significantly higher in 3xTg-AD neurons when compared to control cultures, suggesting that neuronal expression of pro-AD factors can facilitate altered Zn(2+) homeostasis.

Synergistic inhibitory activities of interleukin-10 and dexamethasone on human CD4+ T cells.

BACKGROUND: We have previously demonstrated that interleukin (IL)-10 synergizes with dexamethasone (Dex) in inhibiting proliferation of human T cells, stimulated in an antigen-presenting cell (APC)-dependent manner. Because IL-10 effectively inhibits APC accessory functions, the synergism could have been a result of its effect on APC. We then investigated the effects of Dex and IL-10 on T-cell subpopulations, stimulated in an APC-independent manner. METHODS: CD4 and CD8 T cells were stimulated with anti-CD3, with or without Dex and IL-10, alone or in combination. Proliferation, glucocorticoid (GC) receptor binding, anti-CD3-induced tyrosine phosphorylation, IL-2 production, and expression of IL-2 receptor alpha, beta, and gamma chains were evaluated. The pharmacologic interactions were analyzed using the isobole method. RESULTS: IL-10 synergized with Dex in inhibiting CD4 but not CD8 T-cell proliferation. The synergism was not associated with modifications of GC receptor number or affinity, nor with modifications of anti-CD3-induced tyrosine phosphorylation. IL-10 synergized with Dex in inhibiting IL-2 production and increased Dex inhibitory effect on the expression of the IL-2 receptor alpha chain, which is up-regulated by CD3 stimulation and IL-2. Only Dex inhibited the beta and gamma chain expression, which, interestingly, is not up-regulated by IL-2. IL-2, as well as IL-7 and IL-15, reversed the effects of IL-10 but not those of Dex. CONCLUSIONS: IL-10 synergizes with Dex in inhibiting CD4 T-cell proliferation. Its synergizing effect is mediated by the inhibition of IL-2 production. Dex exerts additional activities, such as the inhibition of beta and gamma chain expression. Therefore, IL-10 could be useful for the enhancement of GC-based immunosuppressive therapies.

Inhibition of cGMP-dependent protein kinases potently decreases neutrophil spontaneous apoptosis.

The signalling pathways mediating neutrophil spontaneous apoptosis are still largely unknown. We report that the indolocarbazole compound KT5823, a specific inhibitor of cGMP-dependent protein kinases (cGK), dose-dependently inhibited spontaneous apoptosis of neutrophils. At the concentration eliciting the maximum effect (8 microM), it decreased apoptosis from 72.42+/-12.79% to 45.86+/-7.22% (p=0.0002, n=6). Similarly, the isoquinoline sulfonamide compound H89, another cGK inhibitor, prevented neutrophil apoptosis. At the concentration eliciting the maximum effect (20 microM), it decreased apoptosis from 72.42+/-12.79% to 31.84+/-10.70% (p=0.0004, n=6). The maximum effect of KT5823 and H89 was comparable to that of GM-CSF and LPS, respectively. Moreover, YC-1, a soluble guanylate cyclase activator, and 4-([3',4',-(methylenedioxy)benzyl]amino)-6-methoxyquinazoline, a specific phosphodiesterase 5 inhibitor, enhanced neutrophil apoptosis, and their effect was antagonised by KT5823. Taken together, these observations highlight a new role of cGK as important mediators of neutrophil spontaneous apoptosis.