caa a22 4500 606176721 CHVBK 20210128100748.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00018-014-1769-y doi (NATIONALLICENCE)springer-10.1007/s00018-014-1769-y BRI2 ectodomain affects Aβ42 fibrillation and tau truncation in human neuroblastoma cells [Elektronische Daten] [M. Del Campo, C. Oliveira, W. Scheper, R. Zwart, C. Korth, A. Müller-Schiffmann, G. Kostallas, H. Biverstal, J. Presto, J. Johansson, J. Hoozemans, C. Pereira, C. Teunissen] Alzheimer's disease (AD) is pathologically characterized by the presence of misfolded proteins such as amyloid beta (Aβ) in senile plaques, and hyperphosphorylated tau and truncated tau in neurofibrillary tangles (NFT). The BRI2 protein inhibits Aβ aggregation via its BRICHOS domain and regulates critical proteins involved in initiating the amyloid cascade, which has been hypothesized to be central in AD pathogenesis. We recently detected the deposition of BRI2 ectodomain associated with Aβ plaques and concomitant changes in its processing enzymes in early stages of AD. Here, we aimed to investigate the effects of recombinant BRI2 ectodomain (rBRI276-266) on Aβ aggregation and on important molecular pathways involved in early stages of AD, including the unfolded protein response (UPR), phosphorylation and truncation of tau, as well as apoptosis. We found that rBRI276-266 delays Aβ fibril formation, although less efficiently than the BRI2 BRICHOS domain (BRI2 residues 113-231). In human neuroblastoma SH-SY5Y cells, rBRI276-266 slightly decreased cell viability and increased up to two-fold the Bax/Bcl-2 ratio and the subsequent activity of caspases 3 and 9, indicating activation of apoptosis. rBRI276-266 upregulated the chaperone BiP but did not modify the mRNA expression of other UPR markers (CHOP and Xbp-1). Strikingly, rBRI276-266 induced the activation of GSK3β but not the phosphorylation of tau. However, exposure to rBRI276-266 significantly induced the truncation of tau, indicating that BRI2 ectodomain can contribute to NFT formation. Since BRI2 can also regulate the metabolism of Aβ, the current data suggests that BRI2 ectodomain is a potential nexus between Aβ, tau pathology and neurodegeneration. Springer Basel, 2014 Alzheimer's disease nationallicence ITM2b nationallicence BRICHOS nationallicence Aggregation nationallicence Fibrillation nationallicence Apoptosis nationallicence Del Campo M. Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Center (VUmc), Room PK1 Br016, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands aut Oliveira C. CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal aut Scheper W. Department of Clinical Genetics and Alzheimer Center, VUmc, Amsterdam, The Netherlands aut Zwart R. Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, VU University, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands aut Korth C. Department of Neuropathology, Heinrich Heine University Medical School, 40225, Düsseldorf, Germany aut Müller-Schiffmann A. Department of Neuropathology, Heinrich Heine University Medical School, 40225, Düsseldorf, Germany aut Kostallas G. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut Biverstal H. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut Presto J. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut Johansson J. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut Hoozemans J. Department of Pathology, VUmc, Amsterdam, The Netherlands aut Pereira C. CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal aut Teunissen C. Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Center (VUmc), Room PK1 Br016, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands aut Cellular and Molecular Life Sciences Springer Basel 72/8(2015-04-01), 1599-1611 1420-682X 72:8<1599 2015 72 18 https://doi.org/10.1007/s00018-014-1769-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1769-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Del Campo M. Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Center (VUmc), Room PK1 Br016, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands aut NATIONALLICENCE 700 1- Oliveira C. CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal aut NATIONALLICENCE 700 1- Scheper W. Department of Clinical Genetics and Alzheimer Center, VUmc, Amsterdam, The Netherlands aut NATIONALLICENCE 700 1- Zwart R. Departments of Functional Genomics and Molecular and Cellular Neuroscience, Center for Neurogenomics and Cognitive Research, VU University, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands aut NATIONALLICENCE 700 1- Korth C. Department of Neuropathology, Heinrich Heine University Medical School, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Müller-Schiffmann A. Department of Neuropathology, Heinrich Heine University Medical School, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Kostallas G. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut NATIONALLICENCE 700 1- Biverstal H. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut NATIONALLICENCE 700 1- Presto J. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut NATIONALLICENCE 700 1- Johansson J. Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, 141 57, Huddinge, Sweden aut NATIONALLICENCE 700 1- Hoozemans J. Department of Pathology, VUmc, Amsterdam, The Netherlands aut NATIONALLICENCE 700 1- Pereira C. CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal aut NATIONALLICENCE 700 1- Teunissen C. Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Center (VUmc), Room PK1 Br016, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/8(2015-04-01), 1599-1611 1420-682X 72:8<1599 2015 72 18