BackgroundGenome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer’s disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD.MethodsIn this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies.ResultsHere, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions.ConclusionOur study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0124-1) contains supplementary material, which is available to authorized users.

Chronic activation of the NF-κB pathway is associated with progressive neurodegeneration in Parkinson’s disease (PD). Given the role of neuronal RING finger protein 11 (RNF11) as a negative regulator of the NF-κB pathway, in this report we investigated the function of RNF11 in dopaminergic cells in PD-associated neurodegeneration. We found that RNF11 knock-down in an in vitro model of PD mediated protection against 6-OHDA-induced toxicity. In converse, over-expression of RNF11 enhanced 6-OHDA-induced dopaminergic cell death. Furthermore, by directly manipulating NF-κB signaling, we showed that the observed RNF11-enhanced 6-OHDA toxicity is mediated through inhibition of NF-κB-dependent transcription of TNF-α, antioxidants GSS and SOD1, and anti-apoptotic factor BCL2. Experiments in an in vivo 6-OHDA rat model of PD recapitulated the in vitro results. In vivo targeted RNF11 over-expression in nigral neurons enhanced 6-OHDA toxicity, as evident by increased amphetamine-induced rotations and loss of nigral dopaminergic neurons as compared to controls. This enhanced toxicity was coupled with down-regulation of NF-κB transcribed GSS, SOD1, BCL2, and neurotrophic factor BDNF mRNA levels, in addition to decreased TNF-α mRNA levels in ventral mesenchephalon samples. In converse, knockdown of RNF11 was associated with protective phenotypes and increased expression of above-mentioned NF-κB transcribed genes. Collectively, our in vitro and in vivo data suggest that RNF11-mediated inhibition of NF-κB in dopaminergic cells exaggerates 6-OHDA toxicity by inhibiting neuroprotective responses while loss of RNF11 inhibition on NF-κB activity promotes neuronal survival. The decreased expression of RNF11 in surviving cortical and nigral tissue detected in PD patients, thus implies a compensatory response in the diseased brain to PD-associated insults. In summary, our findings demonstrate that RNF11 in neurons can modulate susceptibility to 6-OHDA toxicity through NF-κB mediated responses. This neuron-specific role of RNF11 in the brain has important implications for targeted therapeutics aimed at preventing neurodegeneration.

Objectives: Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging and demographics may have affected ICH volumes. The goal of this study was to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. The current study utilizes those data and compares with ICH cases from the same region in 1988. Initial CT images of the head were reviewed, and ICH volumes were calculated using consistent methodology. Results: From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28·8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008-2012, with age-and-race adjusted volume decreasing from 18.3 mL to 13.76 mL (p=0.025). Conclusions: Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008-2012.

No abstract

Objective: Patients on antiplatelet (AP) or anticoagulant (AC) agents cause more alarm when they develop intracerebral hemorrhage (ICH) compared with non-users. This analysis aimed to quantitatively evaluate the differences in the hospital course of ICH patients based on underlying AP and/or AC use, using a population-based cohort. Methods: Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) was a population-based study of spontaneous ICH among residents of the five-county Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. Baseline demographics, medications, hospital course, and discharge disposition were collected. Initial and subsequent computed tomography (CT) images of the head were reviewed to assess ICH location, volume, and presence of intraventricular hemorrhage (IVH). Change in ICH volume was calculated when repeat CT image was available. Results: There were 1121 cases of ICH during the study period. A higher proportion of white patients were on AP or AC than other races (56.4% vs. 39.7%, p<.0001). The majority of patients with subsequent imaging experienced an increase in ICH size. Patients taking AC pre-ICH had a larger increase in volume despite more frequent use of pro-thrombotic therapy. There was no difference in IVH incidence based on AP or AC use. Length of stay and surgical hematoma evacuation rates were similar among the groups. Inpatient mortality was higher in AC users (44.4% vs. 21.3%, p<.0001), but was virtually the same for AP users as for non-users. Of 272 pre-ICH AP users, 86 (31.6%) were discharged on AP (8 on dual AP). Of 91 pre-ICH AC users, 11 (12%) were discharged on AC. Conclusion: Pre-ICH AC use was associated with greater ICH volume increase and inpatient death. There was no significant difference in number of IVH, rate of surgical treatment, or length of stay. Inpatient mortality did not differ between AP users and non-users.