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Sporadic Alzheimer’s disease (AD) is the most common cause of dementia. However, representative experimental models of AD have remained difficult to produce because of the disease’s uncertain origin. The Polycomb group protein BMI1 regulates chromatin compaction and gene silencing. BMI1 expression is abundant in adult brain neurons but down-regulated in AD brains. We show here that mice lacking one allele of Bmi1 (Bmi1+/−) develop normally but present with age cognitive deficits and neurodegeneration sharing similarities with AD. Bmi1+/− mice also transgenic for the amyloid beta precursor protein died prematurely and present aggravated disease. Loss of heterochromatin and DNA damage response (DDR) at repetitive DNA sequences were predominant in Bmi1+/− mouse neurons and inhibition of the DDR mitigated the amyloid and Tau phenotype. Heterochromatin anomalies and DDR at repetitive DNA sequences were also found in AD brains. Aging Bmi1+/− mice may thus represent an interesting model to identify and study novel pathogenic mechanisms related to AD.

Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD.

Objective To determine whether any correlation exists between the phenotype and genotype of 2 Lebanese families with members affected with Wilson disease (WD). Background WD is an autosomal-recessive disorder of copper transport with significant phenotypic diversity. Most patients are compound heterozygous making it difficult to establish a clear link between phenotype and genotype. Study We investigated 14 members from 2 Lebanese families (H and Z) with 5 members affected with WD. Mutation analysis of the ATP7B gene, and clinical assessments were carried out for both families. We also performed a literature search retrieving reported phenotypes of all patients homozygous to mutations in any of the 21 exons of the ATP7B. Results Patients of the H and Z-families were found homozygous for the respective Asn1270Ser and Pro1273Leu mutations in the adenosine triphosphate (ATP) hinge region of exon 18. Of the healthy members, 6 were heterozygous and 3 had normal sequences. Clinically, 4 patients had liver cirrhosis and 1 had asymptomatic transaminitis. One of the patients also had neurologic symptoms. Screening the literature for patients homozygous for mutations in the ATP hinge region identified 25 patients including ours. The overall prevalence of the hepatic phenotype among patients homozygous for mutation in exon 18 was 80% and was significantly higher than those in exons 7, 14, and 21. Conclusions We hereby report the association of liver disease with homozygous mutations in the conserved ATP hinge region of exon 18 of the ATP7B gene.

185 Background: Only a subset of MM patients benefit from treatment with IPI. In an effort to increase response and identify predictive immune biomarkers, we combined IPI with CP. We here report a significant correlation between overall survival (OS) and biomarkers of a pre-existing inflammatory state. Methods: 30 patients were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and IPI (3mg/kg) every 3 weeks x 4. Blood was collected throughout. OS Kaplan–Meier curves were compared by the log-rank test. Cutoff thresholds defining high or low levels of chemokines, B cell populations and PD-1+CD8+ T cell populations were established from the mean value of a given variable from all patients. Neutrophil to Lymphocyte Ratio (NLR) and Systemic Immune Inflammation Index defined as Platelet x Neutrophil to Lymphocyte Ratio (SII) were calculated at baseline and tested for association with OS. SII ≥ 1375 and NLR ≥ 5 were considered as high risk groups. Results: Median OS was 16.2 months, with a 3-year OS of 36.7% for all patients. High levels of CCL3 (HR = 2.79, p = 0.0159), CCL4 (HR = 8.36, p < 0.0001) and CXCL8 (HR = 3.52, p = 0.0037) were associated with worse OS. Advanced B cell differentiation before treatment was associated with worse patient outcomes. High levels of early differentiated Bm2 ( > 57%) were strongly associated with better OS: HR = 0.26 p = 0.004 whereas high eBm5+Bm5 ( > 14%) levels were strongly associated with worse OS: HR = 2.65, p = 0.029. Patients with higher proportions of PD-1+CD8+ T cells in circulation during treatment had poorer OS (HR = 3.84, p = 0.004) at week 10; (HR = 3.53, p = 0.005) at week 13 and (HR = 2.84, p = 0.040) at week 24. High risk SII (HR = 3.30, p = 0.0192) and NLR (HR = 2.367, p = 0.0486) were associated with worse OS. Conclusions: We have identified a significant correlation between pre-existing systemic inflammatory state and a poor response to IPI and CP. Specifically elevated CCL3, CCL4 and CXCL8, baseline B lymphocyte subset skewing, increased CD8+PD-1+ T lymphocytes, increased NLR and SII were all strongly associated to worse OS. Comprehensive immune monitoring provides evidence for new circulating biomarkers predicting outcome in MM patients treated with IPI and CP. Clinical trial information: NCT01676649.

A series of adenine-copper complexes (1-6) with various ligands (Cl(-), SCN(-), BF(4)(-) and acac [acetylacetonate ion]) have been synthesized and characterized by elemental analysis, infrared spectroscopy and thermal analysis. Among the six complexes only complex (1), Cu(2)(adenine)(4)Cl(4).2EtOH (abbreviated as Cu-Ad), demonstrated some toxic effect on different cell lines. In vitro investigations of the biological effect of Cu-Ad complex have shown that it: (1) binds genomic DNA; (2) decreases significantly, the viability of cells in culture in a concentration (15-125 microM)-dependant manner; an estimated IC(50) of: 45 microM with HepG2; 73 microM with C2C12; 103 microM with NIH3T3; and 108 microM with MCF7. Cu-Ad had no effect on A549 cells; (3) inhibits Taq polymerase-catalyzed reaction; (4) inhibits the binding of the transcription factor GATA-5 to labeled DNA probes; (5) inhibits mitochondrial NADH-UQ-reductase with an estimated IC(50) of 2.8 nmol, but had no effect on succinate dehydrogenase activity; (6) increases reactive oxygen species (60%) at 45 microM Cu-Ad; and (7) decreases ATP (80%) at 50 microM Cu-Ad. The new compound Cu(2)(adenine)(4)Cl(4).2EtOH (Cu-Ad), belongs to a class of copper-adenylate complexes that target many biochemical sites and with potential anti-cancer activity.

The polycomb repressive complex 1 (PRC1), containing the core BMI1 and RING1A/B proteins, mono-ubiquitinylates histone H2A (H2A(ub)) and is associated with silenced developmental genes at facultative heterochromatin. It is, however, assumed that the PRC1 is excluded from constitutive heterochromatin in somatic cells based on work performed on mouse embryonic stem cells and oocytes. We show here that BMI1 is required for constitutive heterochromatin formation and silencing in human and mouse somatic cells. BMI1 was highly enriched at intergenic and pericentric heterochromatin, co-immunoprecipitated with the architectural heterochromatin proteins HP1, DEK1, and ATRx, and was required for their localization. In contrast, BRCA1 localization was BMI1-independent and partially redundant with that of BMI1 for H2A(ub) deposition, constitutive heterochromatin formation, and silencing. These observations suggest a dynamic and developmentally regulated model of PRC1 occupancy at constitutive heterochromatin, and where BMI1 function in somatic cells is to stabilize the repetitive genome.

Aging increases the risk to develop several neurodegenerative diseases, although the underlying mechanisms are poorly understood. Inactivation of the Polycomb group gene Bmi1 in mice results in growth retardation, cerebellar degeneration, and development of a premature aging-like phenotype. This progeroid phenotype is characterized by formation of lens cataracts, apoptosis of cortical neurons, and increase of reactive oxygen species (ROS) concentrations, owing to p53-mediated repression of antioxidant response (AOR) genes. Herein we report that Bmi1 expression progressively declines in the neurons of aging mouse and human brains. In old brains, p53 accumulates at the promoter of AOR genes, correlating with a repressed chromatin state, down-regulation of AOR genes, and increased oxidative damages to lipids and DNA. Comparative gene expression analysis further revealed that aging brains display an up-regulation of the senescence-associated genes IL-6, p19(Arf) and p16(Ink4a), along with the pro-apoptotic gene Noxa, as seen in Bmi1-null mice. Increasing Bmi1 expression in cortical neurons conferred robust protection against DNA damage-induced cell death or mitochondrial poisoning, and resulted in suppression of ROS through activation of AOR genes. These observations unveil that Bmi1 genetic deficiency recapitulates aspects of physiological brain aging and that Bmi1 over-expression is a potential therapeutic modality against neurodegeneration.