Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

Defects in interleukin-1ß (IL-1ß)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1ß inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1ß receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

Transplantation of Human Skin-Derived Mesenchymal Stromal Cells Improves Locomotor Recovery After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating neurologic disorder with significant impacts on quality of life, life expectancy, and economic burden. Although there are no fully restorative treatments yet available, several animal and small-scale clinical studies have highlighted the therapeutic potential of cellular interventions for SCI. Mesenchymal stem cells (MSCs)-which are conventionally isolated from the bone marrow-recently emerged as promising candidates for treating SCI and have been shown to provide trophic support, ameliorate inflammatory responses, and reduce cell death following the mechanical trauma. Here we evaluated the human skin as an alternative source of adult MSCs suitable for autologous cell transplantation strategies for SCI. We showed that human skin-derived MSCs (hSD-MSCs) express a range of neural markers under standard culture conditions and are able to survive and respond to neurogenic stimulation in vitro. In addition, using histological analysis and behavioral assessment, we demonstrated as a proof-of-principle that hSD-MSC transplantation reduces the severity of tissue loss and facilitates locomotor recovery in a rat model of SCI. Altogether, the study provides further characterization of skin-derived MSC cultures and indicates that the human skin may represent an attractive source for cell-based therapies for SCI and other neurological disorders. Further investigation is needed to elucidate the mechanisms by which hSD-MSCs elicit tissue repair and/or locomotor recovery.

Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection.

BACKGROUND: Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI. METHODS: Spinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α. RESULTS: LXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4. CONCLUSIONS: Collectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.

Cross-species comparative hippocampal transcriptomics in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-ß (hAß)-KI, have been developed to better resemble sporadic human AD. METHODS: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAß-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. RESULTS: The three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Experimental validation of consistently dysregulated genes revealed five altered in mice (SLC11A1, S100A6, CD14, CD33, and C1QB) and three in humans (S100A6, SLC11A1, and KCNK). Finally, we identified 17 transcription factors potentially acting as master regulators of AD. CONCLUSION: Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hAß-KI being the more specific one.

Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults.

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αß40, Αß42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc-). They practiced 20-40 min daily. Four weeks of practicing the Osc+ and Osc- conditions produced large effect size differences in change in plasma Aß40 and Aß42 levels. The Osc+ condition decreased plasma Αß while the Osc- condition increased Αß. Decreases in Αß were associated with decreases in gene transcription indicators of ß-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc- interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.

Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer's disease.

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome.

Astrocytes: From the Physiology to the Disease.

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.

Neuroprotective effects of lipoxin A4 in central nervous system pathologies.

Many diseases of the central nervous system are characterized and sometimes worsened by an intense inflammatory response in the affected tissue. It is now accepted that resolution of inflammation is an active process mediated by a group of mediators that can act in synchrony to switch the phenotype of cells, from a proinflammatory one to another that favors the return to homeostasis. This new genus of proresolving mediators includes resolvins, protectins, maresins, and lipoxins, the first to be discovered. In this short review we provide an overview of current knowledge into the cellular and molecular interactions of lipoxins in diseases of the central nervous system in which they appear to facilitate the resolution of inflammation, thus exerting a neuroprotective action.

Neuroprotective effect of the proanthocyanidin-rich fraction in experimental model of spinal cord injury.

OBJECTIVES: In this study, we evaluated the effect of the proanthocyanidins-rich fraction (PRF) obtained from Croton celtidifolius bark in an experimental animal model of spinal cord injury and cell death induced by glutamate. METHODS: Experiments were conducted using adult male Wistar rats (10 weeks old and weighing 270-300g). Experimental groups were randomly allocated into the following groups: spinal cord injury (SCI) + vehicle group: rats were subjected to SCI plus intraperitoneal administration of vehicle (saline 10 ml/kg); SCI + PRF: rats were subjected to SCI plus intraperitoneal administration of PRF (10 mg/kg) at 1 and 6 h after injury and sham operated. KEY FINDINGS: The treatment with the proanthocyanidin-rich fraction significantly improved not only motor recovery and grip force but also H2 O2 or glutamate-induced cell death and reactive oxygen species generation induced by glutamate in dorsal root ganglion cells. In this study we demonstrate that the neuroprotective effect triggered by the proanthocyanidins-rich fraction appears to be mediated in part by the inhibition of N-methyl-D-aspartate-type glutamate receptors. CONCLUSIONS: Taken together, our results demonstrate that PRF treatment ameliorates spinal cord injury and glutamatergic excitotoxicity and could have a potential therapeutic use.

Características das pessoas com acidente vascular encefálico atendidas em um centro de referência estadual / Características de las personas con accidente cerebrovascular atendidas em um centro de rehabilitación / Characteristics of encephalic vascular accident patients treated at a state reference center

Encephalic Vascular Accident is a clinical sign of brain dysfunction and it might result in permanent and irreversible lesions. Objective: defined the characteristics such as age, sex and date of the first treatment at a Santa Catarina State’s Rehabilitation Center. Methods: This is a quantitative cross-sectional descriptive study.The Ethnics in Human Research (CEPSH), the Pro Rector for Research and Extension Federal University of Santa Catarina, number 1024 reviewed this study. Results: Stroke affected 25,11% of women between 71-80 years old and 34,09% of the men aged between 61-70 years old. The most common consequence due to stroke was hemiplegia and the study observed that many patients only looked for proper treatment after several years post stroke. Conclusions: The physical therapy is important, so patients can relearn daily tasks and furthermore reintegrate their social life.

Acidente Vascular Encefálico (AVE) é uma disfunção cerebral que causa lesões permanentes e irreversíveis. Objetivo: Avaliar as idades, os sexos e a data do primeiro atendimento das pessoas com AVE atendidas no centro de reabilitação do Estado de Santa Catarina. Métodos: É um estudo quantitativo, descritivo e transversal, sendo a coleta de dados realizada com base documental nos prontuários. O presente estudo foi avaliado pelo Comitê de Ética em Pesquisa com Seres Humanos (CEPSH), Reitoria de Pesquisa e Extensão da Universidade Federal de Santa Catarina de número 1024. Resultados: O AVE afeta 25,11% de mulheres entre 71-80 anos e 34,09% de homens entre 61-70 anos. Observou-se que a sequela mais comum é a hemiplegia e que muitos somente procuravam tratamento após muitos anos de sequelas. Conclusão: Os dados encontrados mostram a importância da terapia física para que os pacientes reaprendam tarefas diárias e auxilia na reintegração social.

El Accidente Cerebrovascular (ACV) es un signo clínico de disfunción cerebral e ocasiona lesiones cerebrales permanentes e irreversibles. Objetivo: Evaluar las edades, sexos y la fecha del tratamiento inicial de los pacientes con accidente cerebrovascular tratados en el centro de rehabilitación en el estado de Santa Catarina. Métodos: El estudio cuantitativo, descriptivo y transversal. Este estudio fue revisado por el Pro Rector de Investigación y Extensión de la Universidad Federal de Santa Catarina para la Investigación Humana (CESPH). La recolección de datos se basó en registros documentales de las personas atendidas en el Centro de Rehabilitación del Estado de Santa Catarina, entre 2000-2009. Resultados: El AVC afecta 25.11% de las mujeres de 71-80 años y el 34,09% de los varones de 61-70 años. La hemiplejia es secuela más común. El estudio destaca que muchos pacientes buscan tratamiento sólo después de muchos años de secuela. Conclusión: Nuestros datos muestran la importancia de la terapia física, ya que permite que los pacientes pueden volver a aprender las tareas cotidianas.

Evaluation of chemical mediators and cellular response during acute and chronic gut inflammatory response induced by dextran sodium sulfate in mice.

Inflammatory bowel disease (IBD) affects millions of people worldwide but its pathophysiology remains unclear. Therefore, experimental models of colitis have contributed crucially for the understanding of IBD, and also in the investigations for effective therapies. Herein we investigated the kinetics of inflammatory mediator production and cell infiltration during acute and chronic dextran sodium sulfate (DSS)-induced colitis. The induction phases with DSS were characterized by severe disease activity with massive colonic polymorphonuclear infiltration and increased levels of tumor necrosis factor-α (TNF-α), keratinocyte-derived chemokine (CXCL1/KC), interleukin (IL)-17 and vascular adhesion molecule-1 (VCAM-1). Interestingly, in the recovery periods, we found marked increase of anti-inflammatory mediators IL-10, IL-4, transforming growth factor-ß (TGF-ß) and cyclooxygenase 2 (COX-2) that seems be essential for the resolution of intestinal inflammation. Furthermore, nuclear factor κB (NFκB) and regulatory T cell marker forkhead box P3 (FoxP3) were increased gradually during experimental colitis, demonstrating a discrepant profile response and evident immune disbalance in the chronic phase of intestinal mucosal inflammation. Taken together, these results provide valuable information for studies on DSS-induced colitis and especially for the identification of biomarkers that predict disease course and possible therapeutic interventions.

Knowing to care: characterization of individuals with spinal cord injury treated at a rehabilitation center / Conhecer para cuidar: caracterização de pessoas com lesão medular atendidas em um centro de reabilitação

Introduction Spinal cord injury (SCI) results in motor, sensory and autonomic dysfunction. The symptoms observed in patients with spinal cord injury will depend on the area affected by the injury. Nursing care is essential for better patient outcomes. Objective The aim of this study was to characterize patients with spinal cord injury treated at a state referral rehabilitation center for SCI. Methods We performed a quantitative cross-sectional descriptive study of 109 patients between the years 2000 and 2009. Results We found a predominance of spinal cord injury in men aged up to 30 years (48.5%). The main causes of spinal cord injuries were traffic accidents. The thoracic region was the most frequently affected site (39.7%), followed by the cervical region (25.6%). Most of the study subjects had been rated as ASIA A, according to the American Spinal Cord Injury Association scale. Discussion These findings corroborate previous studies observing that traffic accidents are the leading causes of spinal cord injury and that people affected by it usually do not seek proper care. Receiving early intervention services and counseling is essential for a better outcome and for achieving an improvement in the quality of life of these patients. Conclusion Despite the increasing incidence of spinal cord injuries nowadays, there is still a lack of data on the subject. The greatest limitation of this study is the incompleteness of medical records, which hindered the access to information. .

Introdução O trauma raquimedular consiste numa agressão à medula espinhal que gera sequelas motoras, sensitivas e autônomas. Os sintomas observados nos pacientes com lesão medular dependem da área lesionada. O cuidado em saúde de enfermagem é essencial para a reabilitação dessas pessoas. Objetivo Caracterizar as pessoas com lesão medular atendidas em um centro de reabilitação de referência estadual. Metodologia Estudo descritivo, quantitativo e transversal de 109 prontuários atendidos entre os anos de 2000 a 2009. Resultados Observou-se a predominância de lesão medular em homens com até 30 anos (48,7%), sendo que os acidentes automobilísticos foram as causas mais frequentes. A região mais acometida é a torácica (39,7%,), seguida pela cervical (25,6%,). A maioria dos indivíduos do estudo apresentava classificação A, de acordo com a escala da American Spinal Cord Injury Association. Discussão A literatura confirma o achado da pesquisa, mostrando que os acidentes de moto e carro são as causas mais frequentes de traumas na coluna e que muitas pessoas, após sofrerem lesão medular, não procuram acompanhamento adequado. As orientações e as intervenções precoces são imprescindíveis para a melhora da qualidade de vida desses pacientes. Conclusão Apesar do aumento da ocorrência de lesão medular na atualidade, observa-se uma escassez de dados sobre o assunto. A maior limitação do estudo são as avaliações incompletas nos prontuários, dificultando o acesso às informações. .