BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

Martin Weber,William F Forrest,Kimberly Scearce-Levie,Chung Kung,Lisa Lima,Daniel Fleck,Ryan J Watts,William J Meilandt,Timothy K Earr,Tiffany Wu,Shannon D Shields,Oded Foreman,Janice A Maloney,Miriam Baca,Sara L Dominguez,Søren Warming,Hilda O Solanoy,Hai Ngu

doi:10.1038/srep44249

Abstract

Assessing BACE1 (β-site APP cleaving enzyme 1) knockout mice for general health and neurological function may be useful in predicting risks associated with prolonged pharmacological BACE1 inhibition, a treatment approach currently being developed for Alzheimer’s disease. To determine whether BACE1 deletion-associated effects in mice generalize to another species, we developed a novel Bace1−/− rat line using zinc-finger nuclease technology and compared Bace1−/− mice and rats with their Bace1+/+ counterparts. Lack of BACE1 was confirmed in Bace1−/− animals from both species. Removal of BACE1 affected startle magnitude, balance beam performance, pain response, and nerve myelination in both species. While both mice and rats lacking BACE1 have shown increased mortality, the increase was smaller and restricted to early developmental stages for rats. Bace1−/− mice and rats further differed in body weight, spontaneous locomotor activity, and prepulse inhibition of startle. While the effects of species and genetic background on these phenotypes remain difficult to distinguish, our findings suggest that BACE1’s role in myelination and some sensorimotor functions is consistent between mice and rats and may be conserved in other species. Other phenotypes differ between these models, suggesting that some effects of BACE1 inhibition vary with the biological context (e.g. species or background strain).

Highlights

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and amyloid plaques in the brain, with hyperphosphorylated tau and amyloid beta (Aβ)peptides as their key components, respectively
We generated and characterized a novel rat Bace1−/− model and directly compared it with an established Bace1−/− mouse model, focusing on behaviors and endpoints that are likely to be modulated by BACE1 activity
This cross-species characterization can highlight potential safety liabilities that may emerge after prolonged pharmacological inhibition of BACE1

Summary

Introduction

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and amyloid plaques in the brain, with hyperphosphorylated tau and amyloid beta (Aβ)peptides as their key components, respectively. The first cleavage step is largely due to the activity of the aspartyl protease BACE1 (β-site APP cleavage enzyme 1), which is widely expressed in the brain (see expression patterns on biogps.org) This suggests that inhibition of BACE1 could prevent or reduce the accumulation of Aβin the brain, reducing AD-related pathology and possibly functional impairments. While Fielden et al.[22] focused on ocular readouts, this raises the more general question of how well other findings in BACE1 null mice may translate to rats and possibly other species, or if they are unique to the mouse species or specific strain in a given study.

Methods

Results

Conclusion