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J Neurosci. 2014 Aug 27;34(35):11621-30. doi: 10.1523/JNEUROSCI.1405-14.2014.

Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice.

Author information

1
Roche Pharmaceutical Research & Early Development, DTA Neuroscience, helmut.jacobsen@roche.com bernd.bohrmann@roche.com.
2
Roche Pharmaceutical Research & Early Development, DTA Neuroscience.
3
Pharmaceutical Sciences, and.
4
Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland, and.
5
reMYND, 3001 Leuven, Belgium.

Abstract

Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.

KEYWORDS:

Alzheimer's disease; Aβ-antibody; BACE; amyloidosis; tg-APP mouse

PMID:
25164658
PMCID:
PMC4145168
DOI:
10.1523/JNEUROSCI.1405-14.2014
[Indexed for MEDLINE]
Free PMC Article

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