Novel players in the aging synapse: impact on cognition

© Mariana Temido-Ferreira, et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.M.T.-F. and J.E.C. were supported by a fellowship from Fundação para a Ciência e Tecnologia (FCT, Portugal); L.V.L is an Investigator CEEC-FCT. P.A.P. is supported by EU Joint Program—Neurodegenerative Disease Research (JPND) project CIRCPROT (jointly funded by BMBF, MIUR, and EU Horizon 2020 grant agreement no. 643417). This study was also funded by Santa Casa da Misericórdia - Mantero Belard 2018 (MB-7-2018) and by UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

Transection of the superior sagittal sinus enables bilateral access to the rodent midline brain structures

Copyright © 2021 Dias et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.Stereotaxic access to brain areas underneath the superior sagittal sinus (SSS) is notoriously challenging. As a major drainage vessel, covering the whole extension of the sagittal fissure, the SSS impedes direct bilateral access to underlying regions for recording and stimulation probes, drug-delivery cannulas, and injection devices. We now describe a new method for transection and retraction of the SSS in rats, that allows the accurate placement of microinjection devices, or chronic electrode probes, while avoiding hemorrhage and the ensuing deleterious consequences for local structures, animal health, and behavior. To demonstrate the feasibility of this approach we evaluated its consequences acutely during surgery, and thereafter during surgical survival, recovery, behavioral testing, as well as postmortem analysis of histologic impact in the related brain structures of male rats. This method provides a new approach enabling direct access for manipulation and recording of activity in brain areas previously obstructed by the SSS.This work was supported by the Bial Foundation Grant 135/18; the Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Grant PTDC/MED-NEU/29325/2017); Prémio Santa Casa-Prémio Mantero Belard (MB-7-2018); and FCT PhD Fellowships PD/PB/114125/2015 and PD/128395/2017, Scientific Employment Contract CEECIND/01497/2017, and Exploratory Grant IF/00201/2013; and an IMM Director’s Fund Awardinfo:eu-repo/semantics/publishedVersio

Clínica de animais exóticos e silvestres

O presente trabalho decorre do estágio curricular, do Mestrado Integrado em Medicina Veterinária da Universidade de Évora, realizado pela autora na área de clínica de animais exóticos, no Centro Veterinario Los Sauces. Visa descrever, as atividades desenvolvidas no decorrer do estágio e avaliar os níveis plasmáticos de Dímero-D e fibrinogénio na investigação de distúrbios tromboembólicos, em Psittacus erithacus. No presente estudo participaram 97 aves distribuídas por três grupos: I) aves clinicamente saudáveis ( =61), II) aves clinicamente doentes com suspeita diagnóstica de distúrbios tromboembólicos ( =13) e III) aves clinicamente doentes, sem evidência de distúrbios tromboembólicos ( =23). As concentrações de Dímero-D foram determinadas pelo teste quantitativo Blue D-Dimer, que utiliza uma metodologia de fluxo imunoturbidimétrico. O valor médio de Dímero-D no grupo I foi 11 ng/mL, no grupo II 3033 ng/mL e no grupo III 1265 ng/mL. Demonstrou-se que os níveis plasmáticos normais de Dímero-D constituem um importante parâmetro na exclusão diagnóstica de distúrbios tromboembólicos; CLINIC OF EXOTIC AND WILDLIFE ANIMALS ABSTRACT: This master's thesis is based in traineeship of the Integrated Master Degree in Veterinary Medicine at the University of Évora, conducted by the author in the clinical field of exotic animals in Centro Veterinario Los Sauces. This work aims describing the developed activities during the internship and evaluating the plasma levels of D-dimer and fibrinogen in Psittacus erithacus. In this study 97 participating birds where distributed in three groups: I) clinically healthy birds ( =61), II) clinically ill birds with thromboembolic disorders diagnostic suspicion ( =13) and III) birds clinically ill, with no evidence of thromboembolic disorders ( =23). The D-dimer concentrations were determined by quantitative test Blue D-dimer, which uses a immunoturbidimetric flow method. The average value of D-dimer in the group I was 11 ng/mL in group II 3033 ng/mL and group III 1265 ng/mL. It has been demonstrated that the normal plasma levels of D-dimer are an important parameter for diagnostic exclusion of thromboembolic disorder

Abdominal Actinomycosis misdiagnosed as liposarcoma

Actinomycosis is an uncommon, endogenous, and chronic infection with varied and nonspecific clinical features such as abdominal, pelvic or cervical masses, ulcerative lesions, abscesses, draining fistula, fibrosis, and constitutional symptoms. The disease ensues when the bacteria disrupt the mucosal barrier, invade, and spread throughout interfascial planes. Currently, the diagnosis of actinomycosis is challenging because of its very low frequency and depending on the clinical presentation it may masquerade malignancies. Therapy consists initially in intravenous penicillin, followed by an oral regimen that may be extended until a year of treatment. A timely diagnosis is crucial to avoid extensive therapeutic attempt as surgery. However, a biopsy or drainage of abscesses and fistula’s tract may be required not only as a diagnostic procedure as part of the therapy. We report the case of a 72-year-old woman with an abdominal mass initially misdiagnosed as a liposarcoma. A second biopsy of a skin lesion of the abdominal wall made the diagnosis of actinomycosis, avoiding a major surgical procedure. The patient was treated with a long-term course of antibiotics with favorable outcome. Liposarcoma was ruled out after the patient’s full recovery with antibiotics and the misdiagnosis was credit to the overconfidence on the immunohistochemical positivity to MDM2

Immunopathology and Trypanosoma congolense parasite sequestration cause acute cerebral trypanosomiasis

© 2022, Silva Pereira, De Niz et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.Trypanosoma congolense causes a syndrome of variable severity in animals in Africa. Cerebral trypanosomiasis is a severe form, but the mechanism underlying this severity remains unknown. We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral, and physiological consequences of this infection. We show large parasite sequestration in the brain vasculature for long periods of time (up to 8 hr) and extensive neuropathology that associate with ICAM1-mediated recruitment and accumulation of T cells in the brain parenchyma. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.This work was supported by European Union’s Horizon 2020 research and innovation program through a Marie Skłodowska-Curie Individual Standard European Fellowship to S.S.P., under grant agreement no. 839960, and from the European Research Council (ERC) (FatTryp, 771714) to L.M.F. M.D.N. was funded by Human Frontiers LT000047/2019 L (HFSP) and EMBO (ALTF 1048–2016). L.M.F., K.S., and C.A.F. are Investigators CEEC of the Fundação para a Ciência e a Tecnologia (CEECIND/03322/2018, CEECIND/00697/2018, CEECIND/04251/2017, respectively). C.A.F. was supported by a European Research Council starting grant (679368), the Fondation Leducq (17CVD03), and the Fundação para a Ciência e a Tecnologia (grants IF/00412/2012, EXPL/BEX- BCM/2258/2013, PRECISE-LISBOA-01–0145-FEDER-016394, PTDC/MED-PAT/31639/2017, PTDC/BIA-CEL/32180/2017).info:eu-repo/semantics/publishedVersio

Adenosine receptors as neuroinflammation modulators: role of A1 agonists and A2A antagonists

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2'-dCCPA (2-chloro-N6-cyclopentyl-2'-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy.This research was funded by Cofinanziamento Assegno di Ricerca Volpini-Marucci, n° FPI400037 and by Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/47778/2014). This work was supported by the University of Camerino (Fondo di ricerca di Ateneo) and by a grant from the Ministry of Research (PRIN N° 2015E8EMCM_008, 2015).info:eu-repo/semantics/publishedVersio

FGF21 mediates the lipid metabolism response to amino acid starvation

Abstract Lipogenic gene expression in liver is repressed in mice upon leucine deprivation. The hormone fi broblast growth factor 21 (FGF21), which is critical to the adaptive metabolic response to starvation, is also induced under amino acid deprivation. Upon leucine deprivation, we found that FGF21 is needed to repress expression of lipogenic genes in liver and white adipose tissue, and stimulate phosphorylation of hormone-sensitive lipase in white adipose tissue. The increased expression of Ucp1 in brown adipose tissue under these circumstances is also impaired in FGF21- defi cient mice. Our results demonstrate the important role of FGF21 in the regulation of lipid metabolism during amino acid starvation. ¿De Sousa-Coelho, A. L., J. Relat, E. Hondares, A. Pérez-Martí, F. Ribas, F. Villarroya, P. F. Marrero, and D. Haro. FGF21 mediates the lipid metabolism response to amino acid starvation

Seleção de área para construção de aterro sanitário no município de Esmeraldas, MG, a partir da utilização de ferramentas de geoprocessamento

O presente trabalho teve como objetivo a utilização de ferramentas de geoprocessamento para a identificação de áreas aptas para a construção de aterro sanitário no município de EsmeraldasMG. Para isso, utilizou-se o cálculo da área ideal de alocação do aterro através da projeção de população e dimensionamento do empreendimento. Além disso, para elaboração do mapa de regiões aptas para a implantação do aterro sanitário utilizou-se a sobreposição dos mapas e a subtração dos buffer’s elaborados para cada variável analisada. Os resultados permitiram verificar seis áreas potenciais para implantação do empreendimento. Dessa forma, visando atenuar a complexidade que envolve a seleção de áreas para a construção de aterros sanitários, os usos de técnicas de geoprocessamento se mostraram uma ferramenta eficaz para a realização da identificação preliminar de áreas ideais para implantação desse tipo de empreendimento

The Neuroprotective Action of Amidated-Kyotorphin on Amyloid β Peptide-Induced Alzheimer’s Disease Pathophysiology

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer’s disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid β peptide (Aβ). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aβ administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aβ-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aβ-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aβ oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aβ caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aβ-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.publishersversionpublishe

A2A adenosine receptor deletion is protective in a mouse model of Tauopathy

© 2016 Macmillan Publishers Limited All rights reserved. This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.This work was supported by grants from France Alzheimer (to DB) and LECMA/Alzheimer Forschung Initiative (to DB and CEM). DB and LVL got a Égide/Pessoa program EU exchange grant. Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de-Calais, FEDER, DN2M, ANR (ADONTAGE and ADORATAU, to DB) and FUI MEDIALZ. We thank the animal facility of IMPRT-IFR114 and M Besegher, I Brion, D Cappe, R Dehaynin, J Devassine, Y Lepage, C Meunier and D Taillieu for transgenic mouse production and animal care, as well as M Basquin, D Demeyer, S Eddarkaoui, H Obriot and M Schneider for support. CL holds a doctoral grant from Lille 2 University, and SB from Région Nord Pas de Calais and CHRU de Lille. VF holds a grant from Région Nord-Pas-de-Calais and Inserm. EF holds a post-doctoral grant from Région Nord-Pas-de-Calais (DN2M). LVL is an Investigator FCT (Fundação para a Ciência e Tecnologia, Portugal).info:eu-repo/semantics/publishedVersio