Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Isolation and analysis of partial cDNA sequence coding for superoxide dismutase in Wuchereria bancrofti.

Molecular characterization of Wuchereria bancrofti is essential to develop suitable anti-filarial drugs and vaccines. We describe here isolation, sequence analysis and cloning of a partial cDNA of an enzyme superoxide dismutase from this parasite. The immunoscreening of a lambda zap W. bancrofti microfilarial (Mf) cDNA library with microfilaremic sera had resulted in the isolation of several seroreactive clones including, WbSOD. This clone contained a 309 bp insert and showed significant nucleotide and deduced amino acid sequence homologies to the superoxide dismutases of other nematode parasites. The antioxidant property of this enzyme may have important contribution in the defense mechanism of the parasite against host immune response.     

Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption.

The endogenous opioid system is implicated in excessive ethanol-drinking behavior. However, the role of individual opioid receptor subtypes in the mechanism underlying excessive ethanol-drinking behavior is not yet well understood. Therefore, we investigated the ability of a selective micro1-opioid antagonist, naloxonazine, to modulate ethanol-drinking behavior and ethanol discrimination in a rat model with the use of ethanol self-administration and drug discrimination paradigms. The effects of naloxonazine (0.001-10 mg/kg) on ethanol intake were examined in Sprague-Dawley rats under conditions of limited access to 10% (wt./vol.) ethanol and ad libitum access to food and water. Pretreatment with high doses of naloxonazine (1-10 mg/kg) significantly reduced ethanol consumption. When the effects of naloxonazine on food intake in free-feeding male rats were examined, naloxonazine (1.8-10 mg/kg) significantly suppressed 24-h food intake. Another group of rats was trained to discriminate ethanol (1.25 g/kg, i.p.) from saline on a fixed-ratio schedule (FR 10), and ethanol dose-response tests were conducted once rats had acquired ethanol-saline discrimination. Injections were given 15 min before ethanol dose-response tests were conducted, and after characterization of the ethanol dose-response curve, the effects of naloxonazine on ethanol discrimination were assessed by administering naloxonazine (0.001-10 mg/kg, i.p.) 15 min before ethanol administration. Treatment with naloxonazine (0.001-1.8 mg/kg, i.p.) before the ED(100) dose of ethanol partially antagonized the discriminative stimulus of ethanol without having any effect on the response rate. The results support the suggestion of involvement of micro1-opioid receptors in the discriminative effects of ethanol and ethanol-drinking behavior.     

DFNA54, a third locus for low-frequency hearing loss

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low- frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction =0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding gene POU4F3 yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region of POU4F3 it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI.     

Early life predictors of adult leisure-time physical inactivity: prospective findings from the 1958 British Birth Cohort

BackgroundLeisure-time physical inactivity has a high prevalence and associated disease burden. Adult inactivity research ignores earlier life factors from which later life influences can originate. We aimed to establish whether early life factors influence adult inactivity.MethodsThe 1958 British Birth Cohort is a nationwide follow-up study of all births during 1 week in March, 1958. The outcome of the present study was leisure-time inactivity, defined as activity frequency of less than once a week, assessed at ages 33 years, 42 years, and 50 years (n=12 776). Early life factors (birth to 16 years) were categorised into three domains (physical, social, behavioural). We assessed stability of inactivity from 33 years to 50 years and associations with adult inactivity using logistic regression of: factors within domains, the three domains combined (ie, multivariable associations), and allowing for adult factors. Missing values were imputed with multiple imputation chained equations.FindingsAt each adult age, about 32% of participants were inactive (31% at 33 years, 34% at 42 years, and 30% at 50 years). 1189 (9%) were inactive at all three ages. In analysis of the three domains simultaneously, factors related to adult inactivity were: short prepubertal stature, poor hand control or physical coordination, and poor cognition (physical); low class at birth, minimal parental education, poor household amenities, parental divorce, and institutional care (social); and inactivity, average or lower sports aptitude, smoking, and externalising and unsociable behaviours (behavioural). Odds ratios for inactivity at age 33 years ranged from 0·86 per SD increase in cognition (95% CI 0·82–0·91) to 1·41 (1·23–1·61) for average or lower sports aptitude. Associations weakened slightly but were mostly maintained after adjustment for adult covariates. After allowing for adult covariates participants with unskilled manual backgrounds had 23% higher odds of inactivity at 50 years than those from professional or managerial backgrounds.InterpretationOur study, based on self-report, focuses only on leisure-time inactivity. However, to have repeat, prospective data on inactivity spanning several decades in adulthood is rare, and leisure-time inactivity is likely to be amenable to modification. Adult inactivity is only moderately stable, providing opportunities for behaviour change. Factors from early life are associated with adult inactivity, allowing for early identification of groups vulnerable to later inactivity.FundingThis work was supported by the Department of Health Policy Research Programme through the Public Health Research Consortium. The Great Ormond Street and University College London Institute of Child Health was supported in part by the Department of Health's National Institute for Health Biomedical Research Centre.