Theranostics 2018; 8(18):4957-4968. doi:10.7150/thno.27868

Research Paper

Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation

Matthias Brendel1, Anna Jaworska2,3, Felix Overhoff1, Tanja Blume1,2, Federico Probst1, Franz-Josef Gildehaus1, Peter Bartenstein1,4, Christian Haass2,4,5, Bernd Bohrmann6, Jochen Herms2,4, Michael Willem5, Axel Rominger1,4,7✉

1. Department of Nuclear Medicine, University Hospital, LMU Munich; Munich, Germany
2. DZNE - German Center for Neurodegenerative Diseases, Munich, Germany
3. Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland
4. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
5. Biomedical Center (BMC), Ludwig-Maximilians-University Munich, 81377 Munich, Germany
6. F. Hoffmann-La Roche, Basel, Switzerland
7. Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.

Abstract

Beta secretase (BACE) inhibitors are promising therapeutic compounds currently in clinical phase II/III trials. Preclinical [18F]-florbetaben (FBB) amyloid PET imaging facilitates longitudinal monitoring of amyloidosis in Alzheimer's disease (AD) mouse models. Therefore, we applied this theranostic concept to investigate, by serial FBB PET, the efficacy of a novel BACE1 inhibitor in the PS2APP mouse, which is characterized by early and massive amyloid deposition.

Methods: PS2APP and C57BL/6 (WT) mice were assigned to treatment (PS2APP: N=13; WT: N=11) and vehicle control (PS2APP: N=13; WT: N=11) groups at the age of 9.5 months. All animals had a baseline PET scan and follow-up scans at two months and after completion of the four-month treatment period. In addition to this longitudinal analysis of cerebral amyloidosis by PET, we undertook biochemical amyloid peptide quantification and histological amyloid plaque analyses after the final PET session.

Results: BACE1 inhibitor-treated transgenic mice revealed a progression of the frontal cortical amyloid signal by 8.4 ± 2.2% during the whole treatment period, which was distinctly lower when compared to vehicle-treated mice (15.3 ± 4.4%, p<0.001). A full inhibition of progression was evident in regions with <3.7% of the increase in controls, whereas regions with >10% of the increase in controls showed only 40% attenuation with BACE1 inhibition. BACE1 inhibition in mice with lower amyloidosis at treatment initiation showed a higher efficacy in attenuating progression to PET. A predominant reduction of small plaques in treated mice indicated a main effect of BACE1 on inhibition of de novo amyloidogenesis.

Conclusions: This theranostic study with BACE1 treatment in a transgenic AD model together with amyloid PET monitoring indicated that progression of amyloidosis is more effectively reduced in regions with low initial plaque development and revealed the need of an early treatment initiation during amyloidogenesis.

Keywords: BACE1 inhibitor, transgenic AD mouse model, [18F]-florbetaben PET, amyloid deposition rate

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How to cite this article:
Brendel M, Jaworska A, Overhoff F, Blume T, Probst F, Gildehaus FJ, Bartenstein P, Haass C, Bohrmann B, Herms J, Willem M, Rominger A. Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation. Theranostics 2018; 8(18):4957-4968. doi:10.7150/thno.27868. Available from http://www.thno.org/v08p4957.htm