The role of A2A receptors in cognitive decline : decoding the molecular shift towards neurodegeneration

Aging is associated with cognitive decline both in humans and animals. Importantly, aging is the main risk factor for nerurodegenerative diseases, namely Alzheimer’s disease (AD), which primarily affects synapses in the temporal lobe and hippocampal formation. In fact, synaptic dysfunction plays a central role in AD, since it drives cognitive decline. Indeed, in age-related neurodegeneration, cognitive decline has a stronger correlation to early synapse loss than neuronal loss in patients. Despite the many clinical trials conducted to identify drug targets that could reduce protein toxicity in AD, such targets and strategies have proven unsuccessful. Therefore, efforts focused on identifying the early mechanisms of disease pathogenesis, driven or exacerbated by the aging process, may prove more relevant to slow the progression rather than the current disease-based models. A recent genetic study discovered a significant association of the adenosine A2A receptor encoding gene (ADORA2A) with hippocampal volume in mild cognitive impairment and Alzheimer’s disease. There is compelling evidence from animal models of a cortical and hippocampal upsurge of adenosine A2A receptors (A2AR) in glutamatergic synapses upon aging and AD. Importantly, the blockade of A2AR prevents hippocampus-dependent memory deficits and synaptic impairments in aged animals and in several AD models. Accordingly, in humans, several epidemiological studies have shown that regular caffeine consumption attenuates memory disruption during aging and decreases the risk of developing memory impairments in AD patients. Together, these data suggest that A2AR might be a good candidate as trigger to synaptic dysfunction in aging and AD. The main goal of this dissertation was then to explore the synaptic function of A2AR in age-related conditions. We have assessed the A2AR expression in human hippocampal slices and found a significant upsurge of A2AR in hippocampal neurons of aged humans, a phenotype aggravated in AD patients. Increased selective expression of A2AR driven by the CaMKII promoter in rat forebrain neurons was sufficient to mimic aging-like memory impairments, assessed by the Morris water maze task, and to uncover an LTD-to-LTP shift in the Schaffer collaterals-CA1 synapse of hippocampus. This shift was due to an increased NMDA receptor gating and associated to increased Ca2+ influx. The mGluR5-NMDAR interplay was identified as a key event in A2AR-induced synaptic dysfunction. Moreover, chronic treatment with an A2AR selective antagonist, orally delivered for one month, rescued the aberrant NMDAR overactivation and the plasticity shift. Importantly, the same LTD-to-LTP shift was observed in memory-impaired aged rats and APP/PS1 mice modeling AD, a phenotype rescued upon A2AR blockade. These data support a key role for over-active hippocampal A2AR in aging and AD-dependent synaptic and cognitive dysfunction and may underlie the significant genetic association of ADORA2A with AD. Importantly, this newly found interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity

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

Mesenteric Panniculitis in Sjögren’s Syndrome: A New Systemic Manifestation to Consider?

The association between mesenteric panniculitis and Sjögren's syndrome, although rare, is starting to be recognized. Usually, mesenteric panniculitis is symptomatic, presenting with either general or gastrointestinal symptoms. Sjögren's syndrome is an autoimmune disease that typically affects secretory glands, but may have serious systemic involvement. We report the case of a 77-year-old patient in whom accidental discovery of asymptomatic mesenteric panniculitis on computed tomography led to the diagnosis of Sjögren's syndrome with several systemic manifestations

Age-related shift in LTD is dependent on neuronal adenosine A(2A) receptors interplay with mGluR5 and NMDA receptors

Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca(2+) influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity

Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: NMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena. Experimental approach: Whole-cell patch-clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5-10 weeks) male Wistar rat hippocampus. Key results: Activation of A2A receptors with CGS 21680 (30 nM) consistently facilitated chemically-evoked NMDA receptor-currents (NMDA-PSCs) and afferent-evoked NMDA-currents (NMDA-EPSCs), an action prevented by an A2A receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H-89 (1 μM). These actions did not reflect facilitation in glutamate release since there was no change in NMDA-EPSCs paired pulse ratio. A2A receptor actions were lost in the presence of an open-channel NMDA receptor blocker, MK-801 (10 μM), but persisted in the presence of memantine, at a concentration (10 μM) known to preferentially block extrasynaptic NMDA receptors. Conclusion and implications: These results show that A2A receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non-pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.Work supported by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa 2020 (Programa Operacional Regional de Lisboa) from PORTUGAL 2020 and Fundação para a Ciência e Tecnologia, (FCT), by an FCT project (PTDC/DTP-FTO/3346/2014), and by a Twinning action (SynaNet) from the EU H2020 programme (project number: 692340). F.M.M. was in receipt of SFRH/BD/89582/2012 FTC fellowship, and D.M.R. is in receipt of a fellowship from Instituto de Medicina Molecular (IMM/BI/38-2017).info:eu-repo/semantics/publishedVersio

Factores clínicos e patológicos de prognóstico em doentes com metástases hepáticas de carcinoma gástrico submetidos a Hepatectomia - Será o padrão de crescimento desmoplásico chave para maior sobrevida?

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaIntroduction: Hepatectomy (Hp) might have a definitive role in the treatment of gastric cancer liver metastases (GCLM), due to poor outcomes of other therapies. However, the factors associated with better prognosis that could assist in adequate patient selection are still a matter of debate. Several pathologic factors, such as the growth pattern, have been associated with prognosis in colorectal cancer liver metastases. In spite of this, these factors have never been investigated in GCLM.Materials and Methods: Clinical and pathological review of 19 consecutive patients that underwent surgical resection with curative intent of GCLM between February 1997 and November 2017 at our department. The population is composed of 13 men with a mean age of 66,3±9,9 years. The metastases had a synchronous presentation in 16 patients and were solitary in 11. The mean size was 33,7±23,8mm. The Hp was major in three and synchronous in seven. Major prognostic factors taken into consideration were the patients’ gender, age and postoperative course, histopathological characteristics of the primary tumor and of the metastases, as well as timing and extent of hepatectomy. 90-day postoperative morbidity was graded according to the Dindo-Clavien classification. Statistical analysis was done with SPSS™ v. 24.0 (log rank, Kaplan-Meier and Cox regression).Results: Median and 5-year overall survival were respectively 16 months and 21,2%. Major morbidity occurred in four patients, mortality in one. Ten patients developed recurrent disease. Major determinants of better prognosis were: metachronous resection; absence of major morbidity; gastric tumors of antrum or body, earlier T stage and of intestinal type; metastases smaller than 20mm and with desmoplastic growth pattern (p<0,05). Discussion: Hp is a valid choice in the treatment of GCLM. Nevertheless, most series have only investigated clinical factors of prognosis. In this study, we confirm several key clinical factors that are associated with a better prognosis. Moreover, in what is an innovative and so far unreported finding, we observed that desmoplastic growth pattern of the liver metastasis, possibly reflecting particular tumor-host interactions, is associated with improved survival.Conclusion: Improvement in survival rates of patients with GCLM is possible with proper selection of patients. Pathologic factors such as growth pattern should prompt further research on tumor-host interactions.Introdução: A Hepatectomia (Hp) pode ter um papel crucial no tratamento de metástases hepáticas de carcinoma gástrico (MHCG), uma vez que outras terapêuticas apresentam resultados insatisfatórios. Contudo, os fatores de melhor prognóstico, que podem permitir uma seleção adequada dos doentes, são ainda controversos. Fatores patológicos, como o padrão de crescimento das metástases, têm vindo a ser associados a prognóstico nas metástases hepáticas de carcinoma colorretal. Porém, estes fatores não foram ainda estudados nas MHCG.Materiais e Métodos: Revisão clínico-patológica de 19 doentes submetidos a cirurgia de resseção de MHCG no nosso Serviço, entre fevereiro de 1997 e novembro de 2017. População composta por 13 homens, com uma idade média de 66,3±9,9, 16 doentes com apresentação síncrona e 11 com nódulo secundário único. O tamanho médio das metástases é de 33,7±23,8mm. A hepatectomia foi major em três doentes e síncrona em sete. Os fatores major de prognóstico avaliados foram o género, a idade, a morbilidade pós-operatória, as características histopatológicas do tumor primário e das metástases, bem como o momento e a extensão da hepatectomia. A morbilidade pós-operatória até ao 90º dia foi definida e gradada de acordo com a classificação de Dindo-Clavien. A análise estatística foi feita com SPSS™ v. 24.0 (log rank, Kaplan-Meier and Cox regression).Resultados: A sobrevida global aos 5 anos foi de 21,2% com mediana de 16 meses. A intervenção levou a morbilidade major em quatro doentes e a uma morte. Dez doentes tiveram recidiva da doença. Os determinantes major de melhor prognóstico foram: resseção metácrona, ausência de morbilidade major, tumores primários localizados no corpo e antro gástricos, tipo intestinal, estadio T mais precoce, metástases menores que 20mm com padrão de crescimento desmoplásico (p<0,05). Discussão: A Hp é uma opção válida no tratamento de MHCG. No entanto, a maioria das séries apenas tem investigado os fatores clínicos de prognóstico, alguns deles confirmados neste estudo. Para além disto, como descoberta nunca antes relatada, observámos que o padrão de crescimento desmoplásico das MHCG está associado a melhor prognóstico, o que poderá resultar de interações entre tumor e hospedeiro.Conclusão: Melhores taxas de sobrevida em doentes com MHCG são possíveis com a correta seleção de doentes. Fatores patológicos, como o padrão de crescimento, devem levar a uma investigação mais profunda de interações entre tumor e hospedeiro