Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

Amyloid precursor protein (APP) and its cleavage fragment Amyloid-β (Aβ) have fundamental roles in Alzheimer’s disease (AD). Genetic alterations that either increase the overall dosage of APP or alter its processing to favour the generation of longer, more aggregation prone Aβ species, are directly causative of the disease. People living with one copy of APP are asymptomatic and reducing APP has been shown to lower the relative production of aggregation-prone Aβ species in vitro. For these reasons, reducing APP expression is an attractive approach for AD treatment and prevention. In this review, we will describe the structure and the known functions of APP and go on to discuss the biological consequences of APP knockdown and knockout in model systems. We highlight progress in therapeutic strategies to reverse AD pathology via reducing APP expression. We conclude that new technologies that reduce the dosage of APP expression may allow disease modification and slow clinical progression, delaying or even preventing onset

Chronic Lymphocytic Leukemia increases the pool of peripheral blood hematopoietic stem cells and skews differentiation

Chronic lymphocytic leukemia (CLL) is an indolent B cell malignancy invariably infiltrating the bone marrow. Although treatment options for patients with advanced disease have significantly improved in the past years, the disease remains incurable and after emergence of therapy resistant disease patients succumb to infections due to secondary bone marrow failure. The underlying mechanisms impairing normal hematopoiesis in patients with CLL are poorly defined.We would like to express our deepest gratitude to patients who donated blood for this research. Samples were obtained with assistance from the Cambridge Blood and Stem Cell Biobank, funded by the Cambridge Cancer Centre and Cambridge Stem Cell Institute. This work was funded by the Cancer Research UK (CRUK; C49940/A17480). I.R. is a senior CRUK fellow. E.L. is supported by a Sir Henry Dale fellowship from Wellcome/Royal Society (107630/Z/15/Z). Research in E.L.’s laboratory is supported by Wellcome, BBSRC, EHA and Royal Society. Research in I.R. and E.L. laboratories is supported by core support grants by Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute

Discrepancies in Parent and Teacher Ratings of Social-Behavioral Functioning of Children With Chromosome 22q11.2 Deletion Syndrome: Implications for Assessment

Children with 22q11.2 deletion syndrome exhibit high rates of social-behavioral problems, creating an area in need of intervention. This study obtained parent and teacher ratings on the CBCL/TRF of 67 children with 22q11DS and 57 controls. Results indicated significant differences in social-behavioral functioning of children with 22q11DS compared to controls, depending on rater type. Parents reported greater internalizing, withdrawal, and social problems in children with 22q11DS while teachers perceived few differences between groups. Correlational analyses indicated weak concordance between parent and teacher reports, with no significant correlations on three summary scales. The findings support the use of multiple informants when evaluating the social-behavioral functioning of children with 22q11DS, and suggest that interpretations based on one informant/setting should be made cautiously

GIFT:Hybrid Museum Experiences through Gifting and Play

he GIFT project develops new approaches to creating hybrid physi-cal-digital visitor experiences in museums. Through design exploration of two concepts focusing on gifting and playful appropriation, the project charts how museums can create a deeper and more meaningful experience by giving visitors the tools to tell their own stories. The project is highly cross-disciplinary com-bining HCI research, artist-led exploration, technology explorations, and experi-ence design in collaboration with museums. Furthermore, the project gathers 10 prominent museums from Europe and the US in an action research project that both serves to ground the prototypes and framework in the needs of museums, while also facilitating the museum sector's need to become 'digital-ready', under-standing and capitalising on digital technology. As the project has progressed through half of its duration, we report on initial findings and how these have shaped our direction of progress

Repetitive behavior profiles: Consistency across autism spectrum disorder cohorts and divergence from Prader–Willi syndrome

Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader–Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score <15. Despite the highly heterogeneous nature, the three ASD samples (UIC, UF and Lam’s) showed a similar pattern of the RBS-R endorsements, and the mean RBS-R scores were not different between the UIC and UF samples. However, higher RRB was noted in the ASD sample compared with the PWS sample, as well as in the PWS subgroup with a SCQ score ≥15 compared with the PWS subgroup with a SCQ score <15. Study limitations include a small sample size, a wide age range of our participants, and not controlling for potential covariates. A future replication study using a larger sample and further investigation into the genetic bases of overlapping ASD and RRB phenomenology are needed, given the higher RRB in the PWS subgroup with a SCQ score ≥15

Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation

10.1371/journal.pgen.1000106PLoS Genetics46

Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development