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Alzheimers Dement. 2017 Jun;13(6):701-709. doi: 10.1016/j.jalz.2016.09.005. Epub 2016 Oct 14.

Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition.

Author information

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.

KEYWORDS:

Alzheimer's disease; BACE1 inhibitor; Biomarker; CSF; Tau; Treatment

PMID:
27750032
DOI:
10.1016/j.jalz.2016.09.005
[Indexed for MEDLINE]

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