Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme

sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid-beta peptide (Abeta) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a beta-site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted Abeta levels when BACE was overexpressed, suggesting that sorLA influences beta-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA-APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-APP complex formation. To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE-APP interactions in cells. We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP

Sport et action publique locale : des initiatives entre concurrence et complémentarité inter-institutionnelles. Le cas de la ville de Mérignac (Gironde)

La rationalisation progressive des politiques sportives territoriales : l'exemple de Mérignac (Gironde). Relations entretenues par la municipalité et les associations sportives pour la pratique sportive, par la collectivité et les établissements scolaires pour les conditions de pratique de l'éducation physique et sportive (EPS)

Research Review: Williams syndrome: A critical review of the cognitive, behavioral, and neuroanatomical phenotype

This review critically examines the research findings which characterize the cognitive, behavioral, and neuroanatomical features of Williams syndrome (WS). This article analyzes 178 published studies in the WS literature covering the following areas: 1) General intelligence, 2) Language skills, 3) Visuospatial and face processing skills, 4) Behavior patterns and hypersociability, 5) Musical abilities, and 6) Brain structure and function. We identify methodological issues relating to small sample size, use and type of control groups, and multiple measures of task performance. Previously described 'peaks' within the cognitive profile are closely examined to assess their veracity. This review highlights the need for methodologically sound studies that utilize multiple comparison groups, developmental trajectories, and longitudinal analyses to examine the WS phenotype, as well as those that link brain structure and function to the cognitive and behavioral phenotype of WS individual