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

Schelle, J., Hasler, L. M., Gopfert, J. C., Joos, T. O., Vanderstichele, H., Stoops, E., Mandelkow, E. M., Neumann, U., Shimshek, D. R., Staufenbiel, M., Jucker, M. Kaeser, S. A.

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

INTRODUCTION: The inhibition of the beta-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 beta (Abeta) precursor protein (APP) transgenic mice. METHODS: APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Abeta 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 Abeta pathology. DISCUSSION: Our results demonstrate that BACE1 inhibition not only reduces Abeta generation but also downstream AD pathophysiology. The tight correlation between Abeta aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of BACE1 inhibitors in current clinical trials.