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).

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

“…2, 3). In agreement with previous findings in mice and rats 32,35,36 , Aβ38, Aβ40, and Aβ42 were significantly decreased in BACE1−/− mouse brains, whereas their levels did not differ significantly between BACE1+/− and wild-type littermates (Fig. 1e–g).…”

“…1a–g). In agreement with previously published results 32,33 , BACE1 protein levels in the brain of BACE1+/− mice were approximately half that of wild-type mice, as analyzed by western blot (Fig. 1a, b).…”

β-Secretase BACE1 Is Required for Normal Cochlear Function

“…However, since the mice are not completely deaf, their hearing phenotype is not plainly obvious, but requires detailed audiometric analysis. In view of our findings, previous studies reporting deficits of BACE1 Ϫ/Ϫ mice in behavioral paradigms that used acoustic stimuli such as prepulse inhibition (Savonenko et al, 2008) and acoustic startle responses (Weber et al, 2017) should be discussed also in consideration of the hearing dysfunction of the mice described here.…”

“…In general, BACE1-deficient mice show increased mortality after birth and decreased body weight as they mature (Dominguez et al, 2005). With respect to the PNS and CNS, BACE1 Ϫ/Ϫ mice display a complex phenotype, which includes, at the behavioral level, increased locomotion and ataxia, spontaneous seizures, schizophrenia-like features and decreased thermal pain thresholds, and, at the network and cellular level, neuronal hyperexcitability, aberrant synaptic transmission, axon guidance defects and impaired axonal myelination (Kandalepas and Vassar, 2014;Weber et al, 2017). Importantly, BACE1 levels are high during neuronal development and, with few exceptions, decline with maturation (Willem et al, 2006).…”

Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells

“…Existing evidence indicates that deposition of Aβ exerts detrimental effects on cerebral blood vessels and impairs endothelial structure and function [ 54 – 56 ]. Since BACE1 is the rate limiting enzyme in the production of Aβ, BACE1 inhibitors have emerged as an attractive therapeutic approach in prevention and treatment of AD [ 21 , 57 , 58 ]. Because α- and β-secretase appear to compete for the intracellular pool of APP, sAPPα is increased upon BACE1 inhibition in neuronal cells [ 20 , 59 ].…”