RESUMEN
Synaptic dysfunction and disconnectivity are core deficits in Alzheimer's disease (AD), preceding clear changes in histopathology and cognitive functioning. Here, the early and late effects of tau pathology induction on functional network connectivity were investigated in P301L mice. Multichannel EEG oscillations were used to compute (1) coherent activity between the prefrontal cortex (PFC) and hippocampus (HPC) CA1-CA3 networks; (2) phase-amplitude cross frequency coupling (PAC) between theta and gamma oscillations, which is instrumental in adequate cognitive functioning; (3) information processing as assessed by auditory evoked potentials and oscillations in the passive oddball mismatch negativity-like (MMN) paradigm. At the end, the density of tau aggregation and GABA parvalbumin (PV+) interneurons were quantified by immunohistochemistry. Early weakening of EEG theta oscillations and coherent activity were revealed between the PFC and HPC CA1 and drastic impairments in theta-gamma oscillations PAC from week 2 onwards, while PV+ interneurons count was not altered. Moreover, the tau pathology disrupted the MMN complex amplitude and evoked gamma oscillations to standard and deviant stimuli suggesting altered memory formation and recall. The induction of intracellular tau aggregation by tau seed injection results in early altered connectivity and strong theta-gamma oscillations uncoupling, which may be exploited as an early electrophysiological signature of dysfunctional neuronal networks.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Cognición , Modelos Animales de Enfermedad , Electroencefalografía , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Ratones , Neuronas/metabolismo , Neuronas/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Ácido gamma-Aminobutírico/metabolismoAsunto(s)
Anemia Hemolítica Autoinmune/diagnóstico , Fiebre/etiología , Imagen por Resonancia Cinemagnética/métodos , Infarto del Miocardio/complicaciones , Anemia Hemolítica Autoinmune/fisiopatología , Diagnóstico Diferencial , Femenino , Fiebre/fisiopatología , Gadolinio , Humanos , Aumento de la Imagen/métodos , Persona de Mediana EdadAsunto(s)
Alopurinol/efectos adversos , Antimetabolitos/efectos adversos , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Cardiomiopatía de Takotsubo/inducido químicamente , Anciano , Técnicas de Imagen Cardíaca/métodos , Erupciones por Medicamentos/diagnóstico , Electrocardiografía , Exantema/diagnóstico , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Cardiomiopatía de Takotsubo/diagnósticoRESUMEN
A 59-year-old diabetic patient was admitted with loss of consciousness and convulsions. Hypercalcaemia and hypoglycaemia were discovered. Computed tomographic and technetium scans revealed a retrosternal paramedian nodule. Radical thymectomy was performed by median sternotomy. Diagnosis of intrathymic parathyroid adenoma was made. One year later the patient had good diabetes control without clinical symptoms.
Asunto(s)
Adenoma/diagnóstico , Coristoma/diagnóstico , Enfermedades Linfáticas/diagnóstico , Glándulas Paratiroides , Neoplasias de las Paratiroides/diagnóstico , Convulsiones/etiología , Neoplasias del Timo/diagnóstico , Femenino , Humanos , Persona de Mediana EdadRESUMEN
We have previously shown that an ecto-NPPase modulates the ATP- and ADP-mediated P2Y(AC)-receptor activation in rat C6 glioma. In the present study, 2MeSADP and Ap(3)A induced no detectable PI turnover and were identified as specific agonists of the P2Y(AC)-receptor with EC(50) values of 250 +/- 37 pM and 1 +/- 0.5 microM, respectively. P2Y(AC)-receptor stimulation increased MAP kinase (ERK1/2) activation that returned to the basal level 4 h after stimulation and was correlated with a gradual desensitization of the P2Y(AC)-purinoceptor. The purinoceptor antagonists DIDS and RB2 blocked MAP kinase activation. An IP(3)-independent Ca(2+)-influx was observed after P2Y(AC)-receptor activation. Inhibition of this influx by Ca(2+)-chelation, did not affect MAP kinase activation. Pertussis toxin, toxin B, selective PKC-inhibitors and a specific MEK-inhibitor inhibited the 2MeSADP- and Ap(3)A-induced MAP kinase activation. In addition, transfection with dominant negative RhoA(Asn19) rendered C6 cells insensitive to P2Y(AC)-receptor-mediated MAP kinase activation whereas dominant negative ras was without effect. Immunoprecipitation experiments indicated a significant increase in the phosphorylation of raf-1 after P2Y(AC)-receptor activation. We may conclude that P2Y(AC)-purinoceptor agonists activate MAP kinase through a G(i)-RhoA-PKC-raf-MEK-dependent, but ras- and Ca(2+)-independent cascade.
Asunto(s)
Adenilil Ciclasas/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Agonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2/metabolismo , Proteínas ras/fisiología , Animales , Activación Enzimática/efectos de los fármacos , Toxina del Pertussis , Proteína Quinasa C/fisiología , Antagonistas del Receptor Purinérgico P2 , Ratas , Células Tumorales Cultivadas , Factores de Virulencia de Bordetella/farmacología , Proteína de Unión al GTP rhoA/fisiologíaRESUMEN
1. Extracellularly added P(1),P(3)-di(adenosine-5') triphosphate (Ap(3)A), P(1),P(4)-di(adenosine-5') tetraphosphate (Ap(4)A), ATP, ADP, AMP and adenosine are growth inhibitory for rat C6 glioma cells. Analysis of nucleotide hydrolysis and the use of nucleotidase inhibitors demonstrated that the latter inhibition is due to hydrolysis of the nucleotides to adenosine. 2. Agonists of the P2Y(AC)(-)-receptor enhance the growth of C6 cells if their hydrolysis to adenosine is inhibited by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). In these conditions, the potency to stimulate cell growth parallels the ranking of the receptor agonists, i.e. 2-methylthioadenosine-5'-diphosphate (2MeSADP)>Ap(3)A>Ap(4)A. ATP and ADP are still hydrolysed in the presence of PPADS and have no proliferative effect on C6 cells. 3. The enhanced growth is due to a P2Y(AC)(-)-receptor-mediated activation of p42/44 mitogen-activated protein kinase (MAPK) as shown by immunoblotting and protein kinase assays for active MAPK and the use of the MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059. 4. The UTP-induced enhancement of the growth of C6 cells is due to activation of MAPK by a PPADS sensitive nucleotide receptor. 5. In conclusion, the effect of nucleotides on the growth of C6 cells is determined by ecto-nucleotidases and by activation of nucleotide receptors. Hydrolysis of nucleotides to adenosine induces growth inhibition while inhibition of the hydrolysis of agonists of the P2Y(AC)(-)-receptor enhances cell growth by activation of MAPK.