Bart De Strooper

Summary

Affiliation: Katholieke Universiteit Leuven
Country: Belgium

Publications

  1. pmc Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice
    Ivo Cristiano Martins
    Switch Laboratory, Flanders Institute for Biotechnology VIB and Vrije Universiteit Brussel, Brussel, Belgium
    EMBO J 27:224-33. 2008
  2. pmc Prion protein in Alzheimer's pathogenesis: a hot and controversial issue
    Iryna Benilova
    Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology VIB, Leuven, Belgium
    EMBO Mol Med 2:289-90. 2010
  3. pmc Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease
    Bart De Strooper
    KULeuven and Flanders Interuniversitary Institute for Biotechnology VIB, Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium
    EMBO Rep 8:141-6. 2007
  4. ncbi request reprint Molecular biology. miRNAs in neurodegeneration
    Sébastien S Hébert
    Center for Human Genetics, VIB and KULeuven, Herestraat 49, Leuven, Belgium
    Science 317:1179-80. 2007
  5. ncbi request reprint Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity
    Sébastien S Hébert
    Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB4 and K U Leuven, 3000 Leuven, Belgium
    Neurobiol Dis 17:260-72. 2004
  6. pmc The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo
    Lujia Zhou
    VIB Center for the Biology of Disease, KULeuven, 3000 Leuven, Belgium
    J Biol Chem 287:25927-40. 2012
  7. pmc Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool
    Annelies Vandersteen
    Switch Laboratory, Flanders Institute for Biotechnology VIB, B 3000 Leuven, Belgium
    J Biol Chem 287:36732-43. 2012
  8. ncbi request reprint Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms
    Mostafa Bentahir
    Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB4 and K U Leuven, Leuven, Belgium
    J Neurochem 96:732-42. 2006
  9. pmc gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease
    Lutgarde Serneels
    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium
    Science 324:639-42. 2009
  10. pmc Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes
    Sébastien S Hébert
    Neuronal Cell Biology and Gene Transfer, CME, Flanders Interuniversity Institute for Biotechnolog, VIB4, and Katholieke Universiteit Leuven, Herestraat 49, Leuven 3000, Belgium
    EMBO Rep 7:739-45. 2006

Detail Information

Publications109 found, 100 shown here

  1. pmc Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice
    Ivo Cristiano Martins
    Switch Laboratory, Flanders Institute for Biotechnology VIB and Vrije Universiteit Brussel, Brussel, Belgium
    EMBO J 27:224-33. 2008
    ..Our findings imply that amyloid plaques are potentially major sources of soluble toxic Abeta-aggregates that could readily be activated by exposure to biological lipids...
  2. pmc Prion protein in Alzheimer's pathogenesis: a hot and controversial issue
    Iryna Benilova
    Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology VIB, Leuven, Belgium
    EMBO Mol Med 2:289-90. 2010
    ....
  3. pmc Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease
    Bart De Strooper
    KULeuven and Flanders Interuniversitary Institute for Biotechnology VIB, Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium
    EMBO Rep 8:141-6. 2007
    ..In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target...
  4. ncbi request reprint Molecular biology. miRNAs in neurodegeneration
    Sébastien S Hébert
    Center for Human Genetics, VIB and KULeuven, Herestraat 49, Leuven, Belgium
    Science 317:1179-80. 2007
  5. ncbi request reprint Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity
    Sébastien S Hébert
    Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB4 and K U Leuven, 3000 Leuven, Belgium
    Neurobiol Dis 17:260-72. 2004
    ..In conclusion, our results suggest that gamma-secretase is a heterogeneous family of protein complexes widely expressed in the adult organism...
  6. pmc The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo
    Lujia Zhou
    VIB Center for the Biology of Disease, KULeuven, 3000 Leuven, Belgium
    J Biol Chem 287:25927-40. 2012
    ..This work provides molecular insights into the function and the pathways in which BACE1 is involved, and it will help to predict or interpret possible side effects of BACE1 inhibitor drugs in current clinical trials...
  7. pmc Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool
    Annelies Vandersteen
    Switch Laboratory, Flanders Institute for Biotechnology VIB, B 3000 Leuven, Belgium
    J Biol Chem 287:36732-43. 2012
    ..Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies...
  8. ncbi request reprint Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms
    Mostafa Bentahir
    Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB4 and K U Leuven, Leuven, Belgium
    J Neurochem 96:732-42. 2006
    ..Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways...
  9. pmc gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease
    Lutgarde Serneels
    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium
    Science 324:639-42. 2009
    ..The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease...
  10. pmc Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes
    Sébastien S Hébert
    Neuronal Cell Biology and Gene Transfer, CME, Flanders Interuniversity Institute for Biotechnolog, VIB4, and Katholieke Universiteit Leuven, Herestraat 49, Leuven 3000, Belgium
    EMBO Rep 7:739-45. 2006
    ..Therefore, inhibition of APP processing to decrease Abeta generation in Alzheimer's disease will not interfere significantly with the function of these genes...
  11. doi request reprint MicroRNA regulation of Alzheimer's Amyloid precursor protein expression
    Sébastien S Hébert
    Center for Human Genetics, KULeuven, Belgium
    Neurobiol Dis 33:422-8. 2009
    ..This possibility is further corroborated by the observation that a statistically significant decrease in miR-106b expression was found in sporadic AD patients...
  12. pmc Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-β production by altering Nicastrin maturation and intracellular localization
    Vasiliki Michaki
    Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, KU Leuven, 3000 Leuven, Belgium
    J Biol Chem 287:1100-11. 2012
    ..Reduced Abca2 levels in mammalian cells in vitro, in Drosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage...
  13. pmc The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants
    Sven Vilain
    VIB Center for Biology of Disease, Katholieke Universiteit Leuven, Leuven, Belgium
    PLoS Genet 8:e1002456. 2012
    ....
  14. doi request reprint LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis
    Samer Matta
    VIB Center for the Biology of Disease, 3000 Leuven, Belgium
    Neuron 75:1008-21. 2012
    ....
  15. doi request reprint Alterations in phosphatidylethanolamine levels affect the generation of Aβ
    Iva Nesic
    Center for Human Genetics, Leuven Institute for Neurodegenerative Diseases, KU Leuven, Leuven, Belgium
    Aging Cell 11:63-72. 2012
    ..These results suggest that modulation of the membrane-soluble domains could be a valuable alternative to reduce excessive Aβ generation...
  16. ncbi request reprint Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
    Diana Dominguez
    Center for Human Genetics, Katholieke Universiteit Leuven and Flanders Interuniversity Institute for Biotechnology VIB4, Herestraat 49, 3000 Leuven, Belgium
    J Biol Chem 280:30797-806. 2005
    ..In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity...
  17. doi request reprint Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity
    Lucia Chávez-Gutiérrez
    Center for Human Genetics, KULeuven, and Department for Molecular and Developmental Genetics, VIB4, Herestraat 49, Leuven, Belgium
    J Biol Chem 283:20096-105. 2008
    ..Consequently, these studies indicate that the main role of the Glu(332) is in the maturation and assembly of gamma-secretase rather than in the recognition of the substrates...
  18. doi request reprint Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency
    Melissa Vos
    VIB Center for the Biology of Disease, Leuven, Belgium
    Science 336:1306-10. 2012
    ..Thus, mitochondrial dysfunction was rescued by vitamin K(2) that serves as a mitochondrial electron carrier, helping to maintain normal ATP production...
  19. pmc The mechanism of γ-Secretase dysfunction in familial Alzheimer disease
    Lucia Chávez-Gutiérrez
    VIB Center for the Biology of Disease, Leuven, Belgium
    EMBO J 31:2261-74. 2012
    ....
  20. ncbi request reprint Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide
    Ira Espuny Camacho
    Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, Vlaams Interuniversitair Instituut voor Biotechnologie and Katholieke Universiteit Leuven, 3000 Leuven, Belgium
    J Neurosci 24:10908-17. 2004
    ..Our results suggest that PPARgamma-controlled mechanisms should be explored further as potential drug targets for Alzheimer's disease treatment...
  21. pmc ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1
    Ragna Sannerud
    Laboratory of Membrane Trafficking, Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium
    Proc Natl Acad Sci U S A 108:E559-68. 2011
    ..It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP...
  22. pmc Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression
    Sébastien S Hébert
    Center for Human Genetics, Katholieke Universiteit Leuven and Department of Molecular and Developmental Genetics, VIB, Herestraat 49 bus 602, B 3000 Leuven, Belgium
    Proc Natl Acad Sci U S A 105:6415-20. 2008
    ..We propose that loss of specific miRNAs can contribute to increased BACE1 and Abeta levels in sporadic AD...
  23. pmc The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex
    Ellen Jorissen
    Center for Human Genetics, Katholieke Universiteit Leuven, Vlaams Instituut voor Biotechnologie VIB, 3000 Leuven, Belgium
    J Neurosci 30:4833-44. 2010
    ..Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP...
  24. pmc Alteration of the microRNA network during the progression of Alzheimer's disease
    Pierre Lau
    VIB Center for the Biology of Disease, Leuven, Belgium Center for Human Genetics, Leuven Institute for Neurodegenerative Disorders LIND University Hospitals Leuven, and University of Leuven, O and N4, Herestraat, Leuven, Belgium
    EMBO Mol Med 5:1613-34. 2013
    ..We provide evidence that miR-132-3p may contribute to disease progression through aberrant regulation of mRNA targets in the Tau network. The transcription factor (TF) FOXO1a appears to be a key target of miR-132-3p in this pathway. ..
  25. doi request reprint PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling
    Vanessa A Morais
    VIB Center for the Biology of Disease, 3000 Leuven, Belgium
    Science 344:203-7. 2014
    ..Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations. ..
  26. pmc Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway
    Cary Esselens
    Membrane Trafficking Laboratory, CME VIB04, Gasthuisberg KU Leuven, 3000 Leuven, Belgium
    J Cell Biol 166:1041-54. 2004
    ..Collectively, PS1 deficiency affects in a gamma-secretase-independent fashion the turnover of TLN through autophagic vacuoles, most likely by an impaired capability to fuse with lysosomes...
  27. doi request reprint Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy
    Dominik M Haddad
    VIB Center for the Biology of Disease, 3000 Leuven, Belgium
    Mol Cell 50:831-43. 2013
    ..Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function...
  28. ncbi request reprint gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation
    An Herreman
    Laboratory for Neuronal Cell Biology, Center for Human Genetics, Gasthuisberg KULeuven and Flanders Interuniversity Institute for Biotechnology VIB, Herestraat 49, 3000 Leuven, Belgium
    J Cell Sci 116:1127-36. 2003
    ..Because the trafficking of nicastrin to the Golgi apparatus is dependent on presenilins, our data point to a central role of presenilin in nicastrin maturation/localization, which could help to partially resolve the 'spatial paradox'...
  29. doi request reprint The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons
    Amantha Thathiah
    Department of Molecular and Developmental Genetics, Vlaams Institute for Biotechnology, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
    Science 323:946-51. 2009
    ..Thus, GPR3 represents a potential therapeutic target for the treatment of Alzheimer's disease...
  30. doi request reprint Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation
    Bruno A Bergmans
    Laboratory of Neuronal Cell Biology and Gene Transfer, Leuven, Belgium
    Stem Cells 28:399-406. 2010
    ..Our stem cell culture provides an excellent tool to circumvent the problem of lack of viability of APP/APLP triple knockout mice and will help to explore the function of this intriguing protein further in vitro and in vivo...
  31. doi request reprint Peroxisome proliferator-activated receptor gamma enhances the activity of an insulin degrading enzyme-like metalloprotease for amyloid-beta clearance
    Ira Espuny-Camacho
    Center for Human Genetics, KU Leuven, Leuven, Belgium
    J Alzheimers Dis 20:1119-32. 2010
    ..We conclude that PPARgamma activates an IDE-like Abeta degrading activity. Our work suggests a drugable pathway that can clear Abeta peptide from the brain...
  32. ncbi request reprint Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex
    Alexandra Tolia
    Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, VIB4 and K U Leuven, Herestraat 49, 3000 Leuven, Belgium
    J Biol Chem 281:27633-42. 2006
    ..Our data suggest the possibility that more selective gamma-secretase inhibitors could be designed...
  33. ncbi request reprint Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin
    Omar Nyabi
    Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB4 and K U Leuven, 3000 Leuven, Belgium
    J Biol Chem 278:43430-6. 2003
    ....
  34. pmc Inhibition of beta-secretase in vivo via antibody binding to unique loops (D and F) of BACE1
    Lujia Zhou
    Department of Molecular and Developmental Genetics, VIB, 3000 Leuven, Belgium
    J Biol Chem 286:8677-87. 2011
    ....
  35. ncbi request reprint Peptides based on the presenilin-APP binding domain inhibit APP processing and Aβ production through interfering with the APP transmembrane domain
    Cary Esselens
    Laboratory for Membrane Trafficking, Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium
    FASEB J 26:3765-78. 2012
    ..In cell-based assays, the peptide strongly suppressed APP shedding, demonstrating that it exerts the inhibitory effect already upstream of γ-secretase, most likely through steric hindrance...
  36. ncbi request reprint Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes
    Hermien Acx
    From the Center for the Biology of Disease, Flemish Institute for Biology VIB, 3000 Leuven, Belgium
    J Biol Chem 289:4346-55. 2014
    ..The qualitative and quantitative differences between different γ-secretase complexes could be used to advance drug development in AD and other disorders. ..
  37. ncbi request reprint BACE1 levels correlate with phospho-tau levels in human cerebrospinal fluid
    Soraia Barão
    VIB Center for the Biology of Disease and Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium
    Curr Alzheimer Res 10:671-8. 2013
    ..BACE1 levels in CSF were well correlated with total-tau and hyperphosphorylated tau levels in the CSF, suggesting that the recorded alterations in BACE1 levels correlate with cell death and neurodegeneration. ..
  38. pmc Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
    Francesc X Guix
    VIB Center for Biology of Disease VIB, Leuven, Belgium
    EMBO Mol Med 4:660-73. 2012
    ..Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ(42) and increased the Aβ(42) /Aβ(40) ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD...
  39. ncbi request reprint Amyloid and tau neuropathology differentially affect prefrontal synaptic plasticity and cognitive performance in mouse models of Alzheimer's disease
    Adrian C Lo
    Laboratory of Biological Psychology and Leuven Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium
    J Alzheimers Dis 37:109-25. 2013
    ....
  40. pmc Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio
    Inna Kuperstein
    Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology VIB, Leuven, Belgium
    EMBO J 29:3408-20. 2010
    ..Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates...
  41. pmc ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase
    Thomas Tousseyn
    Center for Human Genetics, Katholieke Universiteit Leuven K U Leuven, Department for Developmental and Molecular Genetics, and Laboratory of Membrane Trafficking, Vlaams Instituut voor Biotechnologie VIB, K U Leuven, B 3000 Leuven, Belgium
    J Biol Chem 284:11738-47. 2009
    ..Thus, ADAM10 performs a dual role in cells, as a metalloprotease when it is membrane-bound, and as a potential signaling protein once cleaved by ADAM9/15 and the gamma-Secretase...
  42. doi request reprint APLP2 regulates neuronal stem cell differentiation during cortical development
    S Ali M Shariati
    KU Leuven, Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium
    J Cell Sci 126:1268-77. 2013
    ..In summary, our data reveal that APLP2 is specifically required for proper cell cycle exit of neuronal progenitors, and thus has a distinct role in priming cortical progenitors for neuronal differentiation...
  43. doi request reprint β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease
    Amantha Thathiah
    Vlaams Instituut voor Biotechnologie Center for the Biology of Disease, Leuven, Belgium
    Nat Med 19:43-9. 2013
    ..Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease...
  44. pmc A novel strategy for the comprehensive analysis of the biomolecular composition of isolated plasma membranes
    Deepak B Thimiri Govinda Raj
    Department of Molecular and Developmental Genetics VIB11, Laboratory for Membrane Trafficking and Center for Human Genetics KULeuven, Gasthuisberg O and N4, Leuven, Belgium
    Mol Syst Biol 7:541. 2011
    ..Since PM proteins provide many pathologically relevant biomarkers representing two-thirds of the currently used drug targets, this novel technology has great potential for biomedical and pharmaceutical applications...
  45. doi request reprint Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains
    Tomoko Wakabayashi
    Center for Human Genetics, K U Leuven, Herestraat 49, B 3000 Leuven, Belgium
    Nat Cell Biol 11:1340-6. 2009
    ..Thus, these studies suggest that maintenance of the integrity of tetraspanin microdomains contributes to the refinement of proteolytic activity of the gamma-secretase complex...
  46. ncbi request reprint Amyloid-beta precursor protein processing in neurodegeneration
    Valérie Wilquet
    Laboratory for Neuronal Cell Biology and Gene Transfer, K U Leuven and VIB, Department of Human Genetics, Herestraat 49, 3000 Leuven, Belgium
    Curr Opin Neurobiol 14:582-8. 2004
    ..However, the absence of consistent and informative phenotypes in different loss of function animal models make elucidating the molecular actions of the amyloid-beta precursor protein an ongoing challenge...
  47. doi request reprint Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice
    Ina Tesseur
    Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease LIND, University of Leuven, Leuven, Belgium
    Neurobiol Aging 34:1779-89. 2013
    ..Taken together these results provide support for a potential disease-modifying aspect when stimulating central 5-HT4 receptors; however, the complexity of the phenomena warrants further research...
  48. doi request reprint Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of gamma-secretase
    Alexandra Tolia
    Department for Molecular and Developmental Genetics, VIB Vlaams Instituut voor Biotechnologie, Belgium
    J Biol Chem 283:19793-803. 2008
    ..Our data are finally combined to propose a model for the architectural organization and activation of the catalytic site of presenilin...
  49. ncbi request reprint BACE1 and presenilin: two unusual aspartyl proteases involved in Alzheimer's disease
    Diana Ines Dominguez
    Neuronal Cell Biology and Gene Transfer Laboratory, Department of Human Genetics, KU Leuven and VIB4, Leuven, Belgium
    Neurodegener Dis 1:168-74. 2004
    ....
  50. doi request reprint Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: a multi-electrode array study
    Seon Ah Chong
    Bio Electronic Systems, IMEC, Kapeldreef 75, Leuven, Belgium
    Neurobiol Dis 44:284-91. 2011
    ..V717I mice and depressed in biAT mice. The findings demonstrate important synaptic changes that differ considerably in the hippocampal sub-regions already at young age, well before the typical amyloid or tau pathology is evident...
  51. pmc Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain
    Maarten Leyssen
    Laboratory of Neurogenetics, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology VIB and University of Leuven, School of Medicine, Leuven, Belgium
    EMBO J 24:2944-55. 2005
    ..Finally, we also found interactions between APP and the JNK stress kinase cascade. Our findings suggest a role for APP in axonal outgrowth after traumatic brain injury...
  52. ncbi request reprint Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling
    Joachim G Schulz
    Glycobiology and Developmental Genetics, University of Leuven, Leuven, Belgium
    J Biol Chem 278:48651-7. 2003
    ..The cleavage is mediated by presenilin/gamma-secretase complex and negatively regulates the plasma membrane targeting of the transcriptional cofactor CASK...
  53. pmc Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function
    Vanessa A Morais
    Center for Human Genetics, K U Leuven, Leuven, Belgium
    EMBO Mol Med 1:99-111. 2009
    ..As Complex I dysfunction is also implicated in sporadic PD, a convergence of genetic and environmental causes of PD on a similar mitochondrial molecular mechanism appears to emerge...
  54. pmc Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation
    Lujia Zhou
    Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium
    EMBO Mol Med 3:291-302. 2011
    ..We propose to classify the E682K mutation as probable pathogenic awaiting further independent confirmation of its association with AD in other patients...
  55. ncbi request reprint Presenilins in memory, Alzheimer's disease, and therapy
    Els Marjaux
    Laboratory for Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, VIB4, K U Leuven, UZ Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
    Neuron 42:189-92. 2004
    ..The question arises as to what extent these observations should influence our thinking on the pathogenesis of Alzheimer's disease and on strategies to further develop gamma-secretase inhibitors...
  56. ncbi request reprint G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease
    Amantha Thathiah
    Molecular and Developmental Genetics, VIB, Leuven, Belgium
    Sci Signal 2:re8. 2009
    ....
  57. pmc The Drosophila homologue of the amyloid precursor protein is a conserved modulator of Wnt PCP signaling
    Alessia Soldano
    VIB Center for the Biology of Disease, Leuven, Belgium
    PLoS Biol 11:e1001562. 2013
    ..Taken together our data suggest that APPL is the first example of a modulator of the Wnt-PCP pathway specifically required for axon outgrowth...
  58. doi request reprint Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"
    Ina Tesseur
    VIB Center for the Biology of Disease, Leuven, Belgium
    Science 340:924-e. 2013
    ..We were not able to reproduce the described effects in several animal models. Drug formulation appears very critical. Our data call for extreme caution when considering this compound for use in AD patients...
  59. doi request reprint LRRK2 expression is enriched in the striosomal compartment of mouse striatum
    Wim Mandemakers
    Center for Human Genetics, K U Leuven, Belgium
    Neurobiol Dis 48:582-93. 2012
    ..The findings rule out a specific requirement of LRRK2 in striosome genesis but suggest a functional role for LRRK2 in striosomes...
  60. pmc The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor
    Aikaterini S Papadopoulou
    VIB, Leuven, Belgium
    Nat Immunol 13:181-7. 2012
    ..In the absence of Dicer or the miR-29a cluster in the thymic epithelium, expression of the IFN-α receptor by the thymic epithelium was higher, which allowed suboptimal signals to trigger rapid loss of thymic cellularity...
  61. doi request reprint The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
    Iryna Benilova
    Center for Human Genetics and Leuven Institute for Neurodegenerative diseases LIND, University of Leuven, Leuven, Belgium
    Nat Neurosci 15:349-57. 2012
    ..Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field...
  62. ncbi request reprint Gene profiling of hippocampal neuronal culture
    Michal Dabrowski
    Laboratory for Neuronal Cell Biology, Center for Human Genetics, and Department of Electrical Engineering ESAT SCD, Katholieke Universiteit Leuven and VIB Flemish Interuniversity Institute for Biotechnology, Leuven, Belgium
    J Neurochem 85:1279-88. 2003
    ..Our results also demonstrate that a comparison across the two experimental platforms (cDNA microarrays and oligonucleotide chips) and across different biological paradigms is feasible...
  63. ncbi request reprint Nicastrin: gatekeeper of the gamma-secretase complex
    Bart De Strooper
    Center for Human Genetics, VIB4 and KULeuven, 3000 Leuven, Belgium
    Cell 122:318-20. 2005
    ..2005) reveal the function of nicastrin, the largest member of the gamma-secretase complex. They show that the nicastrin extracellular domain is essential for recognition of substrate by the gamma-secretase...
  64. pmc The amyloid-beta precursor protein: integrating structure with biological function
    Constanze Reinhard
    Laboratory for Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Center for Human Genetics, KU Leuven and VIB, Leuven, Belgium
    EMBO J 24:3996-4006. 2005
    ..The biological function of APP itself remains, however, unclear. In the current review, we study in detail the different subdomains of APP and try to assign functional significance to particular structures identified in the protein...
  65. pmc Functional and topological analysis of Pen-2, the fourth subunit of the gamma-secretase complex
    Leen Bammens
    Laboratory for the Research of Neurodegenerative Diseases, Center for Human Genetics, KULeuven, Leuven, Belgium
    J Biol Chem 286:12271-82. 2011
    ..Our study supports the hypothesis that Pen-2 is more than a structural component of the γ-secretase complex and may contribute to the catalytic mechanism of the enzyme...
  66. ncbi request reprint Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex
    Bart De Strooper
    Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, K U Leuven and Flanders Interuniversitary Institute for Biotechnology, VIB4, Leuven, Belgium
    Neuron 38:9-12. 2003
    ..Gamma-Secretase is an interesting but complex drug target that challenges classical thinking about proteolytic processing and intracellular signaling...
  67. pmc Near-infrared 808 nm light boosts complex IV-dependent respiration and rescues a Parkinson-related pink1 model
    Melissa Vos
    VIB Center for the Biology of Disease, Leuven, Belgium KU Leuven, Department of Human Genetics and Leuven Research Institute for Neuroscience and Disease LIND, Leuven, Belgium
    PLoS ONE 8:e78562. 2013
    ..Thus, our data indicate that improvement of mitochondrial function using infrared light stimulation is a viable strategy to alleviate pink1-related defects. ..
  68. doi request reprint Novel research horizons for presenilins and γ-secretases in cell biology and disease
    Bart De Strooper
    Center for Human Genetics, Katholieke Universiteit Leuven, and Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    Annu Rev Cell Dev Biol 26:235-60. 2010
    ..This novel knowledge will help to develop better drugs for Alzheimer's disease and cancer. We critically evaluate literature that proposes presenilin functions outside of the γ-secretase complex...
  69. ncbi request reprint Mitochondria dysfunction and neurodegenerative disorders: cause or consequence
    Vanessa A Morais
    Center for Human Genetics, K U Leuven, Belgium
    J Alzheimers Dis 20:S255-63. 2010
    ..For Alzheimer's disease, the evidence in favor of such a link is more indirect, and mitochondrial dysfunction likely occurs at a later stage of the disorder...
  70. doi request reprint Gamma-secretase and the intramembrane proteolysis of Notch
    Ellen Jorissen
    Center for Human Genetics, KULeuven, Leuven, Belgium
    Curr Top Dev Biol 92:201-30. 2010
    ..Finally we explore the recent insight that there are several gamma-secretase complexes in mammalian and discuss possibilities to use gamma-secretase as a drug target in Alzheimer's disease and cancer...
  71. doi request reprint Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process
    Bart De Strooper
    Center for Human Genetics, K U Leuven and Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    Physiol Rev 90:465-94. 2010
    ..Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder...
  72. ncbi request reprint A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases
    Wim Mandemakers
    Center for Human Genetics, K U Leuven, Department of Molecular and Developmental Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium
    J Cell Sci 120:1707-16. 2007
    ..The emerging evidence clearly demonstrates the crucial role of specific mitochondrial functions in maintaining neuronal circuit integrity...
  73. pmc The secretases: enzymes with therapeutic potential in Alzheimer disease
    Bart De Strooper
    Center for Human Genetics, VIB and KULeuven, Herestraat 49, Leuven, Belgium
    Nat Rev Neurol 6:99-107. 2010
    ..Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions...
  74. doi request reprint Alterations of the microRNA network cause neurodegenerative disease
    Sébastien S Hébert
    Center for Human Genetics, K U Leuven, Herestraat 49 bus 602, B 3000 Leuven, Belgium
    Trends Neurosci 32:199-206. 2009
    ..Thus, miRNAs are moving rapidly center stage as key regulators of neuronal development and function in addition to important contributors to neurodegenerative disorder...
  75. doi request reprint gamma-secretases: from cell biology to therapeutic strategies
    Bruno A Bergmans
    Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium
    Lancet Neurol 9:215-26. 2010
    ....
  76. doi request reprint Structure and function of gamma-secretase
    Alexandra Tolia
    Center for Human Genetics, KULeuven and Department for Developmental and Molecular Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium
    Semin Cell Dev Biol 20:211-8. 2009
    ..Here we review current knowledge about the structure and function of gamma-secretase and discuss the value of these findings for the mechanistic understanding of this unusual protease...
  77. ncbi request reprint Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein
    Erwin Lauwers
    Gene Therapy Program, Katholieke Universiteit Leuven, Leuven, Belgium
    Brain Pathol 13:364-72. 2003
    ..Our data also demonstrate the use of lentiviral vectors to create animal models for neurodegenerative diseases...
  78. doi request reprint The role of G protein-coupled receptors in the pathology of Alzheimer's disease
    Amantha Thathiah
    Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology VIB, Leuven, Belgium
    Nat Rev Neurosci 12:73-87. 2011
    ..Additionally, amyloid-β has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD...
  79. doi request reprint Non-coding RNAs with essential roles in neurodegenerative disorders
    Evgenia Salta
    Centre for Human Genetics and Leuven Institute for Neurodegenerative Disorders LIND, University of Leuven, Leuven, Belgium
    Lancet Neurol 11:189-200. 2012
    ..This emerging field is anticipated to profoundly affect clinical research, diagnosis, and therapy in neurology...
  80. ncbi request reprint Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer's disease
    Diana Ines Dominguez
    Centre for Human Genetics, VIB4 and K U Leuven, Herestraat 49, 3000 Leuven, Belgium
    Trends Pharmacol Sci 23:324-30. 2002
    ..Now, the major question is whether these drugs will work in the clinic...
  81. ncbi request reprint FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction
    Dorothy G Flood
    Department of Neurobiology, Cephalon, Inc, West Chester, PA 19380, USA
    Neurobiol Aging 23:335-48. 2002
    ..The APP(NLh/NLh)/PS-1(P264L/P264L) double gene-targeted mouse represents an animal model that exhibits Abeta deposition without overexpression of APP...
  82. ncbi request reprint In vitro studies of Flemish, Dutch, and wild-type beta-amyloid provide evidence for two-staged neurotoxicity
    Samir Kumar-Singh
    Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born Bunge Foundation, University of Antwerp, B 2610 Antwerp, Belgium
    Neurobiol Dis 11:330-40. 2002
    ....
  83. ncbi request reprint A cell biological perspective on Alzheimer's disease
    Wim Annaert
    Neuronal Cell Biology Laboratory, Flanders Interuniversity Institute for Biotechnology VIB and Catholic University of Leuven, Center for Human Genetics Herestraat 49, Belgium
    Annu Rev Cell Dev Biol 18:25-51. 2002
    ..We discuss the cell biology behind the amyloid and tangle hypothesis for Alzheimer's disease, drawing on the many links to the fields of cell biology and developmental biology that have been established in the recent years...
  84. ncbi request reprint Alzheimer's disease: Mental plaque removal
    Bart De Strooper
    Nature 423:392-3. 2003
  85. ncbi request reprint Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding
    Jonathan D J Wrigley
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK
    J Neurochem 90:1312-20. 2004
    ..Together, these data further incriminate the region around the intramembranous aspartates as the active site of the enzyme, targeted by transition state analogue inhibitors, and highlight the roles of individual residues...
  86. ncbi request reprint Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein
    Xiaorei Sai
    Department of Dementia Research, National Institute for Longevity Sciences, 36 3 Gengo, Morioka, Obu, Aichi 474 8522, Japan
    J Biol Chem 277:12915-20. 2002
    ..Taken together, Herp could be involved in Abeta accumulation, including the formation of senile plaques and vascular Abeta deposits...
  87. pmc Neuronal membrane cholesterol loss enhances amyloid peptide generation
    Jose Abad-Rodriguez
    Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, Orbassano, Italy
    J Cell Biol 167:953-60. 2004
    ....
  88. pmc Attack on amyloid
    Philipp J Kahle
    Department of Biochemistry, Ludwig Maximilians University, Munich, Germany
    EMBO Rep 4:747-51. 2003
  89. ncbi request reprint 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity
    Bruno P Imbimbo
    Research and Development, Chiesi Farmaceutici, Via Palermo 26 A, 43100 Parma, Italy
    J Pharmacol Exp Ther 323:822-30. 2007
    ..CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease...
  90. ncbi request reprint Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44
    Daizo Murakami
    Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Japan
    Oncogene 22:1511-6. 2003
    ..Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/gamma-secretase activity in the functional regulation of adhesion molecules...
  91. pmc Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1
    Omar Nelson
    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    J Clin Invest 117:1230-9. 2007
    ..Our observations are consistent with the potential role of disturbed Ca(2+) homeostasis in Alzheimer disease pathogenesis...
  92. ncbi request reprint Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis
    David E Kang
    Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Cell 110:751-62. 2002
    ..These findings highlight an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis...
  93. pmc ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling
    Karina Reiss
    Biochemical Institute, Christian Albrechts University Kiel, Kiel, Germany
    EMBO J 24:742-52. 2005
    ....
  94. ncbi request reprint Presenilins: members of the gamma-secretase quartets, but part-time soloists too
    Tomoko Wakabayashi
    Department for Developmental and Molecular Genetics, VIB, Leuven
    Physiology (Bethesda) 23:194-204. 2008
    ..Presenilins appear also to exert additional functions outside of the gamma-secretase quartets, which needs further investigation...
  95. ncbi request reprint No endogenous A beta production in presenilin-deficient fibroblasts
    Omar Nyabi
    Nat Cell Biol 4:E164; author reply E165-6. 2002
  96. ncbi request reprint Characterization of lentiviral vector-mediated gene transfer in adult mouse brain
    Veerle Baekelandt
    Gene Therapy Program, Laboratory for Experimental Neurosurgery and Neuroanatomy, Katholieke Universiteit Leuven, Provisorium 1, Minderbroedersstraat 17, B 3000 Leuven, Belgium
    Hum Gene Ther 13:841-53. 2002
    ..In the serum of mice injected with lentiviral vectors a humoral response to vector proteins was detected, but this did not compromise transgene expression. Immune response to the transgene was found only in a minority of the animals...
  97. ncbi request reprint European Alzheimer disease funding
    Jesus Avila
    Centro de Biologia Molecular Severo Ochoa
    Nat Med 12:776-7. 2006
  98. pmc Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations
    Huiping Tu
    Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
    Cell 126:981-93. 2006
    ..The ER Ca(2+) leak function of presenilins is independent of their gamma-secretase activity. Our data suggest a Ca(2+) signaling function for presenilins and provide support for the "Ca(2+) hypothesis of AD."..
  99. ncbi request reprint Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway
    Dragana Spasic
    Laboratory of Membrane Trafficking, Department of Human Genetics, Gasthuisberg, Katholieke Universiteit Leuven VIB11, B 3000 Leuven, Belgium
    J Biol Chem 281:26569-77. 2006
    ..This topology is independently underscored by lysine mutagenesis, cell surface biotinylation, and cysteine derivation strategies and is compatible with the different physiological functions assigned to presenilin-1...
  100. ncbi request reprint The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1
    Stefan F Lichtenthaler
    Massachusetts General Hospital Harvard Medical School, Department of Molecular Biology, Boston, Massachusetts 02114, USA
    J Biol Chem 278:48713-9. 2003
    ..The cleavage occurred at a Leu-Ser peptide bond as identified by mass spectrometry using a synthetic peptide. We conclude that PSGL-1 is an additional substrate for BACE1...
  101. ncbi request reprint Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides
    Yoshifumi Nakaya
    Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga 520 2192, Japan
    J Biol Chem 280:19070-7. 2005
    ....