Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.

Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aß plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aß was detected at 4months in TgAPP and pre-plaque intracellular Aß accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1ß) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.

Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson's disease.

Parkinson's disease (PD) is a motor disorder that involves death of dopaminergic neurons in the substantia nigra pars compacta. Parkin is an autosomal recessive gene that is mutated in early onset PD. We investigated the role of parkin and autophagic clearance in postmortem nigrostriatal tissues from 22 non-familial sporadic PD patients and 15 control samples. Parkin was insoluble with altered cytosolic expression in the nigrostriatum of sporadic PD. Parkin insolubility was associated with lack of degradation of ubiquitinated proteins and accumulation of α-Synuclein and parkin in autophagosomes, suggesting autophagic defects in PD. To test parkin's role in mediating autophagic clearance, we used lentiviral gene transfer to express human wild type or mutant parkin (T240R) with α-Synuclein in the rat striatum. Lentiviral expression of α-Synuclein led to accumulation of autophagic vacuoles, while co-expression of parkin with α-Synuclein facilitated autophagic clearance. Subcellular fractionation showed accumulation of α-Synuclein and tau hyper-phosphorylation (p-Tau) in autophagosomes in gene transfer models, similar to the effects observed in PD brains, but parkin expression led to protein deposition into lysosomes. However, parkin loss of function mutation did not affect autophagic clearance. Taken together, these data suggest that functional parkin regulates autophagosome clearance, while decreased parkin solubility may alter normal autophagy in sporadic PD.

Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines.

Synapse loss induced by amyloid beta (Abeta) is thought to be a primary contributor to cognitive decline in Alzheimer's disease. Abeta is generated by proteolysis of amyloid precursor protein (APP), a synaptic receptor whose physiological function remains unclear. In the present study, we investigated the role of APP in dendritic spine formation, which is known to be important for learning and memory. We found that overexpression of APP increased spine number, whereas knockdown of APP reduced spine density in cultured hippocampal neurons. This spine-promoting effect of APP required both the extracellular and intracellular domains of APP, and was accompanied by specific upregulation of the GluR2, but not the GluR1, subunit of AMPA receptors. In an in vivo experiment, we found that cortical layers II/III and hippocampal CA1 pyramidal neurons in 1 year-old APP-deficient mice had fewer and shorter dendritic spines than wild-type littermates. In contrast, transgenic mice overexpressing mutant APP exhibited increased spine density compared to control animals, though only at a young age prior to overaccumulation of soluble amyloid. Additionally, increased glutamate synthesis was observed in young APP transgenic brains, whereas glutamate levels were decreased and GABA levels were increased in APP-deficient mice. These results demonstrate that APP is important for promoting spine formation and is required for proper spine development.

Etude epidemiologique de 150 cas de neoplasies cervicales depistees par le frottis cervico-vaginal a Bangui

Une etude transversale prospective de 14 mois; portant sur 150 frottis a ete realisee chez des femmes vues en consultation en gynecologie obstetrique a l'hopital communautaire de Bangui. Les prelevements ainsi effectues ont ete colores selon la technique de Harris Schoor et les resultats etaient rendus selon la classification de Bethesda couplee a celle de Richart ou celle de l'OMS. Nous avons enregistre : 71;3 pour cent de lesions de bas grade. 20 pour cent de lesions de haut grade et 8;6 de carcinome invasif. Les lesions condylomateuses virales ont representee 40;7 pour cent. Les facteurs de risque identifies etaient : grossesse multiple rapprochee (p=0;03); antecedents d'infections sexuellement transmissibles (p0;001). Comme cela a deja etait demontre anterieurement l'education sanitaire et le depistage systematique constituent les meilleurs moyens de lutte contre le cancer du col uterin

Spatial distribution and developmental appearance of postjunctional P2X1 receptors on smooth muscle cells of the mouse vas deferens.

P2X1-type purinoceptors have been shown to mediate fast transmission between sympathetic varicosities and smooth muscle cells in the mouse vas deferens but the spatial organization of these receptors on the smooth muscle cells remains inconclusive. Voltage clamp techniques were used to estimate the amplitudes of spontaneous excitatory junction currents (SEJCs) in cells of the vas deferens longitudinal smooth muscle layer. These currents involved the activation of about 6% of the P2X-type channels present on the cell, as compared to whole cell currents produced when isolated smooth muscle cells were exposed to maximal concentrations of either ATP or alpha,beta-MeATP. Immunofluorescence staining of the vas deferens with antibodies against P2X1 receptor showed a diffuse, grainy distribution over the entire membrane of each smooth muscle cell. Anti-P2X1 staining was not markedly clustered beneath anti-SV2-stained sympathetic varicosities. Similar results were obtained for cells in the urinary bladder. During development, P2X1 mRNA was detected as early as embryonic day 15 (E15). Increasing intensities of diffuse immunostaining for P2X1 were observed in the walls of the bladder, tail artery, and aorta from E15 until 6 weeks postnatal. The vas deferens showed increasing intensities of diffuse staining of its smooth muscle layers between 2 and 6 weeks postnatal, consistent with the time-course of development of fast purinergic transmission described previously. Together, the results suggest that the response of smooth muscle of the vas deferens to ATP released from sympathetic varicosities relies on rapidly desensitizing P2X1 receptors, distributed diffusely across the smooth muscle cell surface.