A defective expression or activity of neurotrophic factors, such as brain- and glial-derived neurotrophic factors, contributes to neuronal damage in Huntington’s disease (HD). Here, we focused on transforming growth factor-β (TGF-β1), a pleiotropic cytokine with an established role in mechanisms of neuroprotection. Asymptomatic HD patients showed a reduction in TGF-β1 levels in the peripheral blood, which was related to trinucleotide mutation length and glucose hypometabolism in the caudate nucleus. Immunohistochemical analysis in post-mortem brain tissues showed that TGF-β1 was reduced in cortical neurons of asymptomatic and symptomatic HD patients. Both YAC128 and R6/2 HD mutant mice showed a reduced expression of TGF-β1 in the cerebral cortex, localized in neurons, but not in astrocytes. We examined the pharmacological regulation of TGF-β1 formation in asymptomatic R6/2 mice, where blood TGF-β1 levels were also reduced. In these R6/2 mice, both the mGlu2/3 metabotropic glutamate receptor agonist, LY379268, and riluzole failed to increase TGF-β1 formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-β1 production is associated with HD. Accordingly, reduced TGF-β1 mRNA and protein levels were found in cultured astrocytes transfected with mutated exon 1 of the human huntingtin gene, and in striatal knock-in cell lines expressing full-length huntingtin with an expanded glutamine repeat. Taken together, our data suggest that serum TGF-β1 levels are potential biomarkers of HD development during the asymptomatic phase of the disease, and raise the possibility that strategies aimed at rescuing TGF-β1 levels in the brain may influence the progression of HD.

BackgroundHuntington Disease (HD) is a neurodegenerative disorder resulting from the expansion of polyglutamine stretch in the huntingtin protein (Htt). Mutant HTT (mHtt) leads to progressive impairment of several molecular pathways that have been linked to disease pathogenesis. Defects in the production of a number of neurotrophic factors have been described as important determinants contributing to the development of HD. We have previously demonstrated that production of transforming growth factor-β1 (TGF-β1) is also deregulated in HD. Peripheral levels of TGF-β1 were markedly reduced early in the disease and returned to normal levels with disease severity. However, the cause and the biochemical origin of such abnormalities are still unclear.ResultsWe report here that the abnormal production of peripheral TGF-β1 depends on the changes in the percentage of TGF-β1-producing macrophages along disease course. Variation in the number of TGF-β1-producing macrophages resulted from differential activation state of the same cells, which displayed phenotypic and functional heterogeneity throughout the clinical course of HD. We further demonstrated that, similar to the periphery, the number of TGF-β1-immunoreactive cells in human post-mortem brain with HD, varied with neuropathological changes.ConclusionsOur data indicate that reduced bioavailability of TGF-β1 in the serum of HD subjects is attributable to the variation of the number of TGF-β1-producing macrophages. Macrophages display a differential ability to produce TGF-β1, which reflects diversity in cells polarization throughout the disease course. Besides elucidating the biochemical origin of TGF-β1 fluctuations in HD, our study highlights an interesting parallelism between periphery and central compartment and underlines the potential of TGF-β1 as a possible indicator suitable for prediction of disease onset in HD.

Although platelets may contribute to the inflammatory component in atrial fibrillation (AF), the impact of platelet-leukocyte mixed conjugates has not yet been determined. Seventeen patients with persistent AF (8/9 m/f; mean age 68.1 +/- 2.5 years), not on anticoagulant therapy, were recruited and compared to 34 healthy controls with normal sinus rhythm (16/18 m/f; mean age 60.8 +/- 1.2 years). Platelet-leukocyte mixed conjugates, platelet P-selectin and leukocyte activation markers (CD11b, myeloperoxidase) were measured by flow-cytometry in whole blood both in basal condition and after in vitro ADP/collagen challenge. Plasma D-dimer and soluble P-selectin were also measured. Statistical analyses were performed by Mann-Whitney or Wilcoxon U test for intergroup differences. In AF patients platelet count, as well as platelet P-selectin expression and percent platelet-leukocyte conjugates were all significantly lower both in basal condition and upon activation with ADP/collagen. In contrast, both soluble P-selectin and D-dimer were significantly higher than in controls; white blood cell count and leukocyte activation markers were unchanged. In conclusion, the formation of platelet-leukocyte mixed conjugates was unexpectedly reduced in AF, possibly due to less reactive platelets as a consequence of previous in vivo activation by ongoing formation of trace amounts of thrombin.

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BackgroundHuntington's disease (HD) is a neurodegenerative disorder characterised by hyperkinetic movements (chorea), cognitive and psychiatric dysfunction. The disease is caused by an expanded polyglutamine stretch in huntingtin (Htt). mHtt interferes with different cellular functions increasing susceptibility of neurons to apoptosis, which ultimately results in neurodegeneration of the striatum and cortex. Recent evidence indicates that dopamine signalling is also impaired in HD, suggesting dopaminergic circuitry may be a potential therapeutic target for this disease. The dopaminergic stabiliser pridopidine belongs to a new family of compounds known as dopidines, and is in development for treatment of motor symptoms associated with HD. In Phase IIb and III clinical trials, pridopidine has been shown to improve overall motor function in patients with HD. However, it is not known whether the molecule may exert a neuroprotective effect in brain cells.AimsTo evaluate the potential neuroprotective effect of pridopidine in HD, by investigating whether pridopidine plays a role in the regulation of molecular mechanisms essential for neuronal cell survival.MethodsWe performed in vitro experiments in mouse striatal-derived cells expressing mutant Htt (SThdh111/111) and evaluated cell survival in the presence and absence of pridopidine. SThdh111/111 cells were cultured in apoptotic conditions (serum starvation and/or quinolinic acid), in the presence or absence of pridopidine. Cell survival was detected by Annexin V staining.ResultsPreliminary results indicate that pridopidine protects cells from apoptosis and induces an increase in phosphorylation of the protein kinase ERK1/2, whose activation has been shown to be protective in several HD models.ConclusionsThese findings support the hypothesis that pridopidine exerts a neuroprotective effect in HD models and prompt us to further investigate its potential therapeutic use in HD.