El núcleo incertús y su contribución al control de la oscilación theta hipocámpica

Las oscilaciones cerebrales constituyen un mecanismo para la integración temporal de la actividad de poblaciones neuronales distribuidas. La oscilación theta es característica del estado activado del hipocampo y su contribución resulta fundamental para los procesos cognitivos en que participa esta estructura y que incluyen la integración sensorimotora y los procesos de aprendizaje y memoria. La generación o modulación de esta actividad rítmica están reguladas por un complejo sistema que tiene su origen en el tronco del encéfalo y en el que intervienen de manera crítica estructuras del prosencéfalo basal y del diencéfalo. En el tegmento pontino, el núcleo incertus (NI) presenta proyecciones sobre las principales estructuras implicadas en el control de esta oscilación, lo que nos ha llevado a considerar su posible integración en el sistema tegmental de modulación de la activación hipocámpica. En un estudio previo, nuestro grupo verificó además que la estimulación de NI es capaz de generar ritmo theta en el hipocampo en ratas anestesiadas con uretano. En el trabajo de tesis que se presenta se muestra la existencia de una ruta directa desde el principal generador reticular de la oscilación, el núcleo reticularis pontis oralis, hasta el marcapasos de la oscilación, el complejo septum medial-banda diagonal mediante un estudio de inyección doble de trazadores neuronales. Además, se ha profundizado en la implicación de este núcleo en la activación de la oscilación hipocámpica. Para ello, en ratas anestesiadas con uretano, se ha realizado el registro de la actividad neuronal en NI en condiciones espontáneas y en condiciones de generación de ritmo theta en el hipocampo. El estudio de su influencia ha incluido también el análisis del efecto de su lesión o inhibición sobre la oscilación hipocámpica. Por otra parte, se ha estudiado la actividad local de campo en NI y su correlación con la hipocámpica en distintas condiciones de activación, con el objetivo de analizar si NI forma parte del sistema de estructuras que presentan una oscilación sincronizada con la del hipocampo. La actividad de NI ha sido estudiada también en ratas con electrodos implantados crónicamente. En éstas, se ha analizado tanto la actividad neuronal como la actividad eléctrica local de campo y su correlación con la sincronización hipocámpica en distintos estados de activación a lo largo del ciclo de sueño/vigilia. Los resultados obtenidos permiten afirmar que NI está implicado en la generación de la actividad theta hipocámpica y que, en determinadas condiciones, resulta necesario para que ésta se origine. Tanto en el animal anestesiado como en el ciclo de sueño/vigilia, la actividad neuronal en NI se correlaciona con estados activados del hipocampo. Además, se ha podido observar actividad rítmica a frecuencias theta en NI, que en determinadas condiciones tiene lugar a la misma frecuencia que en el hipocampo, con el que muestra una elevada coherencia. En conjunto, el trabajo presentado apoya la inclusión de NI como estructura clave en el sistema de control de la oscilación hipocámpica.Brain oscillations provide a mechanism for temporal integration of distributed neuronal populations. Theta oscillation is characteristic of the hippocampal active state participates in cognitive processes, including sensorymotor integration, learning and memory. Theta rhythm occurs during active wakefulness and it is also characteristic of the REM sleep EEG pattern. A complex system is involved in the generation or modulation of this oscillation, arising from the brainstem and critically involving the basal forebrain and hypothalamus. In the pontine tegmentum, the nucleus incertus (NI) projects to the main structures controlling theta rhythm. This has led us to postulate the implication of NI in the brainstem control of the oscillation. Firstly, the present dissertation analyzes the existence of a neuronal pathway from the main pontine generator - the reticularis pontis oralis nucleus (RPO) - to the septal pacemaker of the rhythmicity through the NI. Moreover, the contribution of the NI in the modulation of the hippocampal function has been assessed in urethane-anaesthetized and chronically implanted rats. Single unit recordings, NI lesion and inhibition have been performed in order to analyze its relevance in theta generation. In addition, we also investigated this field activity in the NI. The results of the present study confirm the implication of the NI in theta rhythm generation. Under anaesthesia, NI neurons were activated in theta periods. In the unanaesthetized rats, NI neurons were most active during active waking, coincidently with hippocampal theta. The lowest neuronal activity was found during non-REM sleep, while in REM, the activity resulted similar to quiet waking. NI lesion or inhibition suppressed RPO-elicited theta oscillation in the hippocampus, but not theta induced by tail-pich. In addition, NI exhibited a rhythmical activity in its local field potential very close in frequencies with the hippocampus both in the anesthetized and unanaesthetized animals. The dissertation suggests the integration of NI in the brainstem network responsible for theta rhythm activation. Together with other structures belonging to the ascending reticular activating system, the NI could influence on the cognitive processes depending on the behavioural state. In conclusion, the study presents evidences for considering NI a key structure in theta circuitry

NeuroLab: Sistema de adquisición y análisis de registros neurofisiológicos

El registro de la actividad eléctrica extracelular constituye el método principal de análisis del comportamiento y función de neuronas y redes neuronales en estudios experimentales invasivos. Se describe un nuevo programa, NeuroLab, desarrollado para la adquisición, visualización y análisis de este tipo de registros. Permite obtener ficheros de hasta 16 canales de campo, unitarios y estimulación. Se han incluido funciones básicas para facilitar al usuario la comprobación de la adquisición correcta, tanto durante la misma (reproducción visual y acústica) como posteriormente mediante opciones de procesado digital. Su concepción modular permite incrementar sus prestaciones añadiendo nuevas funciones a las ya existentes, y el procesado posterior de los datos adquiridos amplía las posibilidades de análisis de este tipo de estudios frente a soluciones comerciales cerradas

Obesity as a Risk Factor for Alzheimer’s Disease: Implication of Leptin and Glutamate

Obesity is known to induce leptin and insulin resistance. Leptin is a peptide hormone synthesized in adipose tissue that mainly regulates food intake. It has been shown that insulin stimulates the production of leptin when adipocytes are exposed to glucose to encourage satiety; while leptin, via a negative feedback, decreases the insulin release and enhances tissue sensitivity to it, leading to glucose uptake for energy utilization or storage. Therefore, resistance to insulin is closely related to leptin resistance. Obesity in middle age has also been related to Alzheimer’s disease (AD). In recent years, the relation between impaired leptin signaling pathway and the onset of AD has been studied. In all this context the role of the blood brain barrier (BBB) is crucial. Slow excitotoxicity happens in AD due to an excess of the neurotransmitter glutamate. Since leptin has been shown to regulate N-methyl-D-aspartate (NMDA) receptors, we want to review the link between these pathological pathways, and how they are affected by other AD triggering factors and its role in the onset of AD

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

The Effectiveness of Vitamin E Treatment in Alzheimer’s Disease

Vitamin E was proposed as treatment for Alzheimer’s disease many years ago. However, the effectiveness of the drug is not clear. Vitamin E is an antioxidant and neuroprotector and it has anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer’s disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer’s. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer’s disease? In this paper we review the studies with and without positive results in Alzheimer’s disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not