title: Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition.
abstract: BACKGROUND
  The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein (APP) transgenic mice.
  
  
  METHODS
  APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed.
  
  
  RESULTS
  We demonstrate that long-term BACE1 inhibition prevents CSF tau increase both in early-depositing APP transgenic mice and APP transgenic mice with moderate Aβ pathology.
  
  
  CONCLUSIONS
  Our results demonstrate that BACE1 inhibition not only reduces Aβ generation but also downstream AD pathophysiology. The tight correlation between Aβ aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of BACE1 inhibitors in current clinical trials.
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schelle
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany; Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Häsler
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Göpfert
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Joos
authors.affiliation: ADx NeuroSciences, Gent, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vanderstichele
authors.affiliation: ADx NeuroSciences, Gent, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Stoops
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany; CAESAR Research Center, Bonn, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
authors.affiliation: CAESAR Research Center, Bonn, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.affiliation: Novartis Institutes for BioMedical Research, Neuroscience, Basel, Switzerland.
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. Electronic address: mathias.jucker@uni-tuebingen.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. Electronic address: stephan.kaeser@uni-tuebingen.de.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007118:Immunoassay; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010848:Picolinic Acids / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013843:Thiazines / Q000494:pharmacology*; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C558298:Mapt protein, mouse; C000605932:NB-360; D010848:Picolinic Acids; D013843:Thiazines; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; BACE1 inhibitor; Biomarker; CSF; Tau; Treatment