title: BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats.
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).
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Meilandt
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Dominguez
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hilda O
authors.initials: HO
authors.lastname: Solanoy
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Maloney
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Baca
authors.affiliation: Department of Transgenic Technology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Chung
authors.initials: C
authors.lastname: Kung
authors.affiliation: Department of Transgenic Technology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lima
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Earr
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fleck
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Shields
authors.affiliation: Department of Bioinformatics, 1 DNA Way, Genentech, South San Francisco, CA 94080, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D065808:Prepulse Inhibition / Q000235:genetics / Q000502:physiology; D051381:Rats; D013216:Reflex, Startle / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat