RESUMEN
AIMS: The present study analyses molecular characteristics of the locus coeruleus (LC) and projections to the amygdala and hippocampus at asymptomatic early and middle Braak stages of neurofibrillary tangle (NFT) pathology. METHODS: Immunohistochemistry, whole-transcriptome arrays and RT-qPCR in LC and western blotting in hippocampus and amygdala in a cohort of asymptomatic individuals at stages I-IV of NFT pathology were used. RESULTS: NFTs in the LC increased in parallel with colocalized expression of tau kinases, increased neuroketal adducts and decreased superoxide dismutase 1 in neurons with hyperphosphorylated tau and decreased voltage-dependent anion channel in neurons containing truncated tau were found. These were accompanied by increased microglia and AIF1, CD68, PTGS2, IL1ß, IL6 and TNF-α gene expression. Whole-transcriptome arrays revealed upregulation of genes coding for proteins associated with heat shock protein binding and genes associated with ATP metabolism and downregulation of genes coding for DNA-binding proteins and members of the small nucleolar RNAs family, at stage IV when compared with stage I. Tyrosine hydroxylase (TH) immunoreactivity was preserved in neurons of the LC, but decreased TH and increased α2A adrenergic receptor protein levels were found in the hippocampus and the amygdala. CONCLUSIONS: Complex alteration of several metabolic pathways occurs in the LC accompanying NFT formation at early and middle asymptomatic stages of NFT pathology. Dopaminergic/noradrenergic denervation and increased expression of α2A adrenergic receptor in the hippocampus and amygdala occur at first stage of NFT pathology, suggesting compensatory activation in the face of decreased adrenergic input occurring before clinical evidence of cognitive impairment and depression.
Asunto(s)
Locus Coeruleus/metabolismo , Locus Coeruleus/patología , Ovillos Neurofibrilares/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-ß-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aß(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimer's disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic surface penetrate the cytoplasm of cultured cells, and they reach the brain when administered intranasally. Both cationic G4mOS and electroneutral G4mDS are able to modify the total burden of ß-amyloid in APP/PS1 mice. The studied dendrimers did not reverse memory impairment in APP/PS1 mice following chronic administration; moreover, cationic G4mOS caused cognitive decline in nontransgenic mice. In spite of the capacity of G4mDS and G4mOS to cross the blood-brain barrier and modulate Aß aggregation in APP/PS1 mice, further studies are needed to learn how to reduce the harmful effects of maltose dendrimers in vivo.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Dendrímeros/farmacología , Glicoconjugados/farmacología , Polipropilenos/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Administración Intranasal , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Supervivencia Celular/efectos de los fármacos , Dendrímeros/administración & dosificación , Dendrímeros/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glicoconjugados/administración & dosificación , Glicoconjugados/química , Humanos , Masculino , Maltosa/química , Ratones , Ratones Transgénicos , Tamaño de la Partícula , Polipropilenos/administración & dosificación , Polipropilenos/química , Proteínas Serina-Treonina Quinasas/genética , Relación Estructura-Actividad , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
Recently, we have shown the expression of novel chemoreceptors corresponding to the olfactory receptor (OR) and taste receptor (TASR) families in the human brain. We have also shown dysregulation of ORs and TASRs in the cerebral cortex in Parkinson's disease. The present study demonstrates the presence of OR mRNA and mRNA of obligated downstream components of OR signaling adenylyl cyclase 3 (ADYLC3) and olfactory G protein (Gnal) in the cerebral cortex of the mouse. Dysregulation of selected ORs and TASRs has been found in the entorhinal cortex and frontal cortex in Alzheimer's disease (AD) in a gradient compatible with Braak and Braak staging; frontal cortex in terminal stages of Progressive Supranuclear Palsy; and frontal cortex and cerebellum in Creutzfeldt-Jakob disease subtypes methionine/methionine at codón 129 of PRNP (MM1) and valine/valine at codón 129 of PRNP (VV2). Altered OR, ADYLC3 and Gnal mRNA expression with disease progression has also been found in APP/PS1 transgenic mice, used as a model of AD. The function of these orphan receptors is not known, but probably related to cell signaling pathways responding to unidentified ligands. Variability in the drift, either down- or up-regulation, of dysregulated genes, suggests that central ORs and TASRs are vulnerable to variegated neurodegenerative diseases with cortical involvement, and that altered expression of ORs and TASRs is not a mere reflection of neuronal loss but rather a modulated pathological response.
Asunto(s)
Enfermedad de Alzheimer/genética , Corteza Cerebral/metabolismo , Síndrome de Creutzfeldt-Jakob/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Odorantes/metabolismo , Parálisis Supranuclear Progresiva/genética , Adenilil Ciclasas/genética , Animales , Cerebelo/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Lóbulo Frontal/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/genética , Ratones , Ratones Transgénicos , Red Nerviosa/patología , ARN Mensajero , Transducción de Señal/genética , Gusto , Regulación hacia ArribaRESUMEN
Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1(+/-) and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1(+/-) mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), and inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered "molecular context" underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed.
Asunto(s)
Depresión/genética , Trastorno Depresivo/genética , Lóbulo Frontal/metabolismo , Ácido Glutámico/genética , Estrés Psicológico/genética , Proteína 1 de Transporte Vesicular de Glutamato/genética , Animales , Conducta Animal , Depresión/fisiopatología , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis por Micromatrices , Trastornos del Humor/genética , Neurotransmisores/genética , Neurotransmisores/metabolismo , Fenotipo , Placer , ARN/análisis , Estrés Psicológico/metabolismo , Sacarosa , Factores de Tiempo , Proteína 1 de Transporte Vesicular de Glutamato/deficiencia , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of >10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience.
Asunto(s)
Depresión/genética , Trastorno Depresivo/genética , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica , Animales , Ansiedad/genética , Depresión/metabolismo , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trastornos del Humor/genética , Placer/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/genética , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
By May 1996, 43 cases of Creutzfeldt-Jakob disease with cadaveric dura transplantation were reported during a nationwide survey in Japan. With the assumption that the number of patients receiving the transplantation each year was 20,000, the incidence of the disease among patients receiving cadaveric dura grafts was compared with the annual incidence in the general population. Cumulative incidence was between 0.017 and 0.048%. The estimated relative maximum risk was 104.9, and even the minimum relative risk was as high as 29.2.