Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic ␣-secretase cleavage of APP, producing secreted APP (sAPP␣), and glycogen synthase kinase (GSK)-3␤ is known to increase tau phosphorylation. Both PKC and GSK-3␤ are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPP␣ production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3␤. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.

Presenilin 1 (PS1) regulates ␤-catenin stability; however, published data regarding the direction of the effect are contradictory. We examined the effects of wildtype and mutant forms of PS1 on the membrane, cytoplasmic, nuclear, and signaling pools of endogenous and exogenous ␤-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of ␤-catenin when stabilized by Wnt or Dvl but not when stabilized at lower levels of the Wnt pathway. The PS1 mutants examined were less able to reduce the stability of ␤-catenin. PS1 also inhibited the transcriptional activity of endogenous ␤-catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl. The transcriptional activity of exogenously expressed wild-type ␤-catenin and two mutants, ⌬N89␤-catenin and ⌬ST␤-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of ␤-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3␤ mediated degradation of ␤-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of ␤-catenin.

IntroductionThe UK Pharmaceutical Industry is arguably one of the most important industries to consider in the negotiations following the Brexit vote. Providing tens of thousands of jobs and billions in tax revenue and research investment, the importance of this industry cannot be understated. At stake is the global leadership in the sector, which produces some of the field’s most influential basic science and translation work. However, interruptions and losses may occur at multiple levels, affecting patients, researchers, universities, companies and government.GoalsBy understanding the current state of pharmaceutical sector, the potential effect of leaving the European Union (EU) on this successful industry can be better understood. This paper aims to address the priorities for negotiations by collating the analyses of professionals in the field, leading companies and non-EU member states.Research methodsA government healthcare policy advisor and Chief Science Officer (CSO) for a major pharmaceutical firm were consulted to scope the paper. In these discussions, five key areas were identified: contribution, legislative processes, regulatory processes, research and outcomes, commercial risk. Multiple search engines were utilised for selecting relevant material, predominantly PubMed and Google Scholar. To supplement this information, Government documents were located using the “GOV.UK” publications tool, and interviews and commentaries were found through the Google News search function.ConclusionWith thorough investigation of the literature, we propose four foundations in the advancement of negotiations. These prioritise: negotiation of ‘associated country’ status, bilaterally favourable trade agreements, minimal interruption to regulatory bodies and special protection for the movement of workforce in the life sciences industry.