Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer’s Disease in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process

KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca(2+)-activated K(+) channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma

Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington's Disease

Rats which receive injections of kainic acid (KA) into the striatum show many of the anatomical, biochemical and behavioral abnormalities seen in patients with Huntington's disease. Recently, it has been reported that fetal striatal transplants into the lesioned striatum could normalize the neurological and behavioral abnormalities produced by the KA lesion. The present study examined the issue of transplant integration in producing behavioral recovery. In one experiment, lesioned animals with transplants located within the lateral ventricle were compared against parenchymally transplanted rats. It was found that unless the ventricular transplant grew into the lesioned striatum there was no recovery. The second experiment demonstrated that electrolytic destruction of a successful fetal striatal transplant could reverse the transplant-induced behavioral recovery. These results suggest that the integrity of the transplant is important in maintaining behavioral recovery. A continuing functional interaction between the host brain and transplanted tissue may be a vital element in the success of the fetal striatal transplant

Caracterização da violência contra crianças e adolescentes

Violence against children and adolescents has been perpetrated over the years and with the emergence of programs for the protection of these victims, there has been an increase in the notification of cases of abuse, mainly practiced by parents in the home environment. Among the numerous risk factors present in violence against children and adolescents are parents with emotional or financial instability, unemployment, low educationlevel and drugs use. These types of violence can be psychological, physical, sexual, negligent or sexually exploited. This article aims to identify the violence committed against. La violencia contra los niños y adolescentes se ha perpetrado a lo largo de los años y, con el surgimiento de programas para proteger a estas víctimas, se ha incrementado la notificación de casos de maltrato, principalmente practicado por los padres en el ámbito familiar. Entre los numerosos factores de riesgo presentes en la violencia contra los niños y adolescentes se encuentran los padres con inestabilidad emocional o económica, el desempleo, la baja escolaridad y el consumo de drogas. Dicha violencia puede ser psicológica, física, sexual, negligencia o explotación sexual. Este artículo tiene como objetivo identificar las violencias cometidas contra niños y adolescentes, caracterizar el perfil del agresor y de la víctima y analizar los cambios de comportamiento en víctimas de maltrato.A violência contra crianças e adolescentes tem se perpetrado ao longo dos anos e, com o surgimento de programas para a proteção dessas vítimas, houve o aumento da notificação de casos de maus-tratos, sendo principalmente praticados pelos progenitores em ambiente domiciliar. Dentre os inúmeros fatores de risco presentes na violência contra crianças e adolescentes estão os pais com instabilidade emocional ou financeira, desemprego, baixa escolaridade e uso de drogas. Essas violências podem ser de teor psicológico, físico, sexual, por negligência ou por exploração sexual. O presente artigo tem como objetivo identificar as violências cometidas contra as crianças e adolescentes, caracterizar o perfil do agressor e da vítima e analisar as mudanças de comportamento nas vítimas dos maus-tratos

Familiality of behavioral flexibility and response inhibition deficits in autism spectrum disorder (ASD)

This work is licensed under a Creative Commons Attribution 4.0 International License.Background Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD. Methods We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+). Results Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP− parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively. Conclusion Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits