Juliane Schelle1, Lisa M Häsler2, Jens C Göpfert3, Thomas O Joos3, Hugo Vanderstichele4, Erik Stoops4, Eva-Maria Mandelkow5, Ulf Neumann6, Derya R Shimshek7, Matthias Staufenbiel8, Mathias Jucker9, Stephan A Kaeser10. 1. 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. 2. 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. 3. Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany. 4. ADx NeuroSciences, Gent, Belgium. 5. DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany; CAESAR Research Center, Bonn, Germany. 6. CAESAR Research Center, Bonn, Germany. 7. Novartis Institutes for BioMedical Research, Neuroscience, Basel, Switzerland. 8. Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 9. 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. 10. 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.
Abstract
INTRODUCTION: 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. DISCUSSION: 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.
INTRODUCTION: 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. DISCUSSION: 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.
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