Peripheral Routes to Neurodegeneration : Passing Through the Blood–Brain Barrier

A bidirectional crosstalk between peripheral players of immunity and the central nervous system (CNS) exists. Hence, blood–brain barrier (BBB) breakdown is emerging as a participant mechanism of dysregulated peripheral–CNS interplay, promoting diseases. Here, we examine the implication of BBB damage in neurodegeneration, linking it to peripheral brain-directed autoantibodies and gut–brain axis mechanisms. As BBB breakdown is a factor contributing to, or even anticipating, neuronal dysfunction(s), we here identify contemporary pharmacological strategies that could be exploited to repair the BBB in disease conditions. Developing neurovascular, add on, therapeutic strategies may lead to a more efficacious pre-clinical to clinical transition with the goal of curbing the progression of neurodegeneration.Peer reviewe

Editorial: Environmental clues to brain disease

International audienceBrain disease represents one of the major social and economic burden worldwide. Identifying the factors impacting brain homeostasis, as well as the mechanisms involved in this deregulation, constitutes a paramount research challenge. If several pathologies have been associated to specific genetic mutations, many other elements contribute to the development of a broad panel of brain diseases. In this Research Topic we collected articles that are analyzing ground-breaking subjects shedding light on the interaction between environment and brain health. Here is a summary of the main findings highlighted in the topic

Regional differential effects of the novel histamine H3 receptor antagonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-Nmethyl-3-pyridinecarboxamide hydrochloride (GSK189254) on histamine release in the central nervous system of freely

ABSTRACT After oral administration, the nonimidazole histamine H 3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H 3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components. The discovery of the histamine H 3 receptor (H 3 R) back in 1983 was a major scientific breakthrough that provided key new perspectives in histamine researc

Energy Drink e Alcool: un cocktail pericoloso

Frequente e diffuso è l’uso di sostanze stimolanti fra la popolazione, specialmente fra i preadolescenti e gli adolescenti. Gli Energy Drink contengono sostanze stimolanti come la Caffeina a dosaggi variabili dai 20 ai 50 mg % ml, associati a Taurina ed estratti vegetali. La Caffeina, il composto biologicamente più attivo in questi Energy Drink, è una sostanza stimolante il sistema nervoso centrale aumentando i livelli di AMP ciclico e anche inibendo l’azione della Adenosina. L’uso cronico, determina assuefazione e dipendenza producendo una sindrome da astinenza. Un uso acuto a dosaggi superiori a 300 mg può determinare una intossicazione con sintomi eccitatori sia a carico del sistema nervoso che dell’apparato cardiocircolatorio. Sono stati riportati anche casi mortali. L’uso di queste bevande è in continuo incremento, come dimostra il fatturato dell’industria alimentare. Spesso i giovani utilizzano queste bevande in associazione ad alcol per tollerarlo meglio e soprattutto per poterne bere ancora di più

Heterogeneity of Histaminergic Neurons

International audienc

Caractérisation immunohistologique de la pathologie amyloïde et des symptômes associés dans un modèle murin dela maladie d'Alzheimer. (Conférencière invitée)

International audienc

Développement d'une méthode automatique de suivi de la croissance de Borrelia burgdorferi

National audienceBorrelia (ou Borreliella) burgdorferi (Bb) est l’agent infectieux responsable de la maladie de Lyme. Même si de nombreuses études ont été conduites sur cet organisme, beaucoup de question reste sans réponse concernant sa physiologie et sa pathogénicité. En effet, la culture de Bb présente de nombreuse difficultés. Par exemple, la méthode standard de suivi de croissance de Bb actuelle est un dénombrement manuel au microscope utilisant une chambre de comptage de Petroff Hausser, ce qui demande du temps et présente une certaine variabilité. Dans cette étude, nous proposons une méthode alternative, plus rapide et automatisée, représentant une amélioration qui pourra permettre d’accélérer les études dans ce champs de recherche

Développement d'une méthode automatique de suivi de la croissance de Borrelia burgdorferi

National audienceBorrelia (ou Borreliella) burgdorferi (Bb) est l’agent infectieux responsable de la maladie de Lyme. Même si de nombreuses études ont été conduites sur cet organisme, beaucoup de question reste sans réponse concernant sa physiologie et sa pathogénicité. En effet, la culture de Bb présente de nombreuse difficultés. Par exemple, la méthode standard de suivi de croissance de Bb actuelle est un dénombrement manuel au microscope utilisant une chambre de comptage de Petroff Hausser, ce qui demande du temps et présente une certaine variabilité. Dans cette étude, nous proposons une méthode alternative, plus rapide et automatisée, représentant une amélioration qui pourra permettre d’accélérer les études dans ce champs de recherche

Serotonin: a new hope in Alzheimer's disease?

International audienceAlzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enhance serotonin concentration in the synaptic cleft have been debated as possible therapeutic strategies to slow the progression of AD. In this Viewpoint, we discuss exciting new insights regarding the modulation of serotonin signaling for AD prevention and therapy

In Vivo Differential Brain Clearance and Catabolism of Monomeric and Oligomeric Alzheimer’s Aβ protein

Amyloid β (Aβ) is the major constituent of the brain deposits found in parenchymal plaques and cerebral blood vessels of patients with Alzheimer’s disease (AD). Several lines of investigation support the notion that synaptic pathology, one of the strongest correlates to cognitive impairment, is related to the progressive accumulation of neurotoxic Aβ oligomers. Since the process of oligomerization/fibrillization is concentration-dependent, it is highly reliant on the homeostatic mechanisms that regulate the steady state levels of Aβ influencing the delicate balance between rate of synthesis, dynamics of aggregation and clearance kinetics. Emerging new data suggest that reduced Aβ clearance, particularly in the aging brain, plays a critical role in the process of amyloid formation and AD pathogenesis. Using well-defined monomeric and low molecular mass oligomeric Aβ1-40 species stereotaxically injected into the brain of C57BL/6 wild-type mice in combination with biochemical and mass spectrometric analyses in CSF, our data clearly demonstrate that Aβ physiologic removal is extremely fast and involves local proteolytic degradation leading to the generation of heterogeneous C-terminally cleaved proteolytic products, while providing clear indication of the detrimental role of oligomerization for brain Aβ efflux. Immunofluorescence confocal microscopy studies provide insight into the cellular pathways involved in the brain removal and cellular uptake of Aβ. The findings indicate that clearance from brain interstitial fluid follows local and systemic paths and that in addition to the blood-brain barrier, local enzymatic degradation and the bulk flow transport through the choroid plexus into the CSF play significant roles. Our studies highlight the diverse factors influencing brain clearance and the participation of various routes of elimination opening up new research opportunities for the understanding of altered mechanisms triggering AD pathology and for the potential design of combined therapeutic strategies