One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0567-4) contains supplementary material, which is available to authorized users.
The properties of the hyperpolarization-activated cation current (Ih) were investigated in rat periglomerular dopaminergic neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. At 37 °C and minimizing the disturbance of the intracellular milieu with perforated patches, this current shows a midpoint of activation around −82.7 mV, with a significant level of opening already at rest, thereby giving a substantial contribution to the resting potential, and ultimately playing a relevant function in the control of the cell excitability. The blockage of Ih has a profound influence on the spontaneous firing of these neurons, which result as strongly depressed. However the effect is not due to a direct role of the current in the pacemaker process, but to the Ih influence on the resting membrane potential. Ih kinetics is sensitive to the intracellular levels of cAMP, whose increase promotes a shift of the activation curve towards more positive potentials. The direct application of DA and 5-HT neurotransmitters, physiologically released onto bulbar dopaminergic neurons and known to act on metabotropic receptors coupled to the cAMP pathway, do not modifythe Ih amplitude. On the contrary, noradrenaline almost halves the Ih amplitude. Our data indicate that the HCN channels do not participate directly to the pacemaker activity of periglomerular dopaminergic neurons, but influence their resting membrane potential by controlling the excitability profile of these cells, and possibly affecting the processing of sensory information taking place at the entry of the bulbar circuitry.
Dopaminergic (DA) periglomerular (PG) neurons are critically placed at the entry of the bulbar circuitry, directly in contact with both the terminals of olfactory sensory neurons and the apical dendrites of projection neurons; they are autorhythmic and are the target of numerous terminals releasing a variety of neurotransmitters. Despite the centrality of their position, suggesting a critical role in the sensory processing, their properties -and consequently their function- remain elusive. The current mediated by inward rectifier potassium (Kir) channels in DA-PG cells was recorded by adopting the perforated-patch configuration in thin slices; IKir could be distinguished from the hyperpolarization-activated current (Ih) by showing full activation in <10 ms, no inactivation, suppression by Ba2+ in a typical voltage-dependent manner (IC50 208 μM) and reversal potential nearly coincident with EK. Ba2+ (2 mM) induces a large depolarization of DA-PG cells, paralleled by an increase of the input resistance, leading to a block of the spontaneous activity, but the Kir current is not an essential component of the pacemaker machinery. The Kir current is negatively modulated by intracellular cAMP, as shown by a decrease of its amplitude induced by forskolin or 8Br-cAMP. We have also tested the neuromodulatory effects of the activation of several metabotropic receptors known to be present on these cells, showing that the current can be modulated by a multiplicity of pathways, whose activation in some case increases the amplitude of the current, as can be observed with agonists of D2, muscarinic, and GABAA receptors, whereas in other cases has the opposite effect, as it can be observed with agonists of α1 noradrenergic, 5-HT and histamine receptors. These characteristics of the Kir currents provide the basis for an unexpected plasticity of DA-PG cell function, making them potentially capable to reconfigure the bulbar network to allow a better flexibility.
Fine-needle aspiration cytology (FNAC) is a minimally invasive procedure usually well tolerated, easy to perform, quick, cheap and easy to repeat in case of doubts or non-diagnostic results. Echography is also a fast, cheap and non-invasive tool; however, the role of FNAC and echography in the diagnosis of salivary gland pathology is not universally recognised. Three hundred and fifty-seven patients with a cytological diagnosis at FNAC, and 247 of these who were also studied with echography, were enrolled for this retrospective study. The final histopathological diagnoses, obtained after surgery, were then compared to the preoperative FNAC diagnoses and echographic findings. From the analysis of our data, the overall FNAC specificity resulted 93%, sensitivity 83%, and diagnostic accuracy 92%. Echography sensibility was 57.1% specificity 98.2%, while positive and negative predictive value were respectively 80% and 94.8%. While echography can be useful in order to provide a better characterization of salivary gland lesions, FNAC can then be considered a safe diagnostic tool with reliable sensitivity and specificity for the assessment of salivary gland pathology and thus for selecting patients and indicating the best surgical treatment.It has been reported that major salivary gland tumours represent approximately 3% of all head and neck tumours; 80% involve parotid gland and 75% are benign neoplasms (l). According to the most recent WHO histological classification (2005) there is a broad spectrum of different histotypes of major salivary gland tumours (2), thus it is necessary to make a correct preoperative diagnosis in order to decide the best surgical/therapeutical approach. In this way, in order to perform a correct preoperative assessment, we used fine needle aspiration cytology (FNAC) and echography.FNAC is a minimally invasive method that does not require anaesthesia; it is well tolerated by the patient, easy to perform, quick, with rare complications, cheap and can be easily repeated in case of doubts or non-diagnostic results in order to reach a more accurate diagnosis (3). Echography is also a fast, cheap and non invasive tool. However, the role of FNAC and echography in the diagnosis of salivary gland pathology is not universally recognised (4, 5). Since its use is still controversial, most ENT surgeons prefer intraoperative frozen section examination to preoperative FNAC (6-7).The aim of this study is to show the accuracy and reliability of FNAC for the diagnosis of benign and malign tumours of major salivary glands through the evaluation of its diagnostic accuracy-sensibility,
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