Species: Mouse
Genes: Bace1
Modification: Bace1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: BACE1^fl/fl available through Robert Vassar; R26CreER^T2 available through The Jackson Laboratory Stock# 008463, Live

Summary

These transgenic mice were designed to mimic BACE1 inhibition, while avoiding the developmental effects of Bace1 deficiency that are seen in germline knock-outs. They were generated by crossing mice with a floxed Bace1 gene to mice carrying a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus. Upon administration of tamoxifen, Bace1 expression is abolished throughout the body.  In the mice described here, tamoxifen was administered at 3 months of age. (Hereafter, these mice are referred to as “BACE1-deficient mice.”)

Unless stated otherwise, this description refers to comparisons between BACE1-deficient mice and mice homozygous for the floxed Bace1 gene that do not express Cre recombinase, but were administered tamoxifen at 3 months of age (hereafter “control”).

There was no difference in mortality in BACE1-deficient mice and controls between 3 and 9 months of age. Glucose and insulin metabolism, feeding, drinking, locomotor activity, energy expenditure, and fuel utilization, measured at 10 months of age, were similar in the two genotypes, although BACE1-deficient mice gained weight faster than did controls (the physiological basis of this weight gain is currently unknown). Major organs (brain, heart, liver, lung, pancreas, spleen, kidney, stomach/intestines, muscle, skin, thymus/lymph nodes) were histologically normal in 12-month-old mice.

BACE1 levels in the cortices and hippocampi of 12-month-old BACE1-deficient mice were reduced by more than 90 percent; this loss of BACE1 was accompanied by increased levels of full-length BACE1 substrates (APP, CHL1, Sez6, also increased APP α-CTF) and lower levels of BACE1 cleavage products (cleaved CHL1, NRG1, Sez6). However, there was residual expression of BACE1 in sub-cortical regions and in the olfactory bulb, perhaps due to variations in penetrance of tamoxifen into different brain regions.

When tested at 9 months of age, BACE1-deficient mice exhibited normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning. A greater number of arm entries in the Y maze may reflect hyperactivity in novel situations.

Long-term potentiation at Schaffer collateral–CA1 synapses was similar in slices obtained from 12-month-old BACE1-deficient and control mice.

Hypomyelination, spontaneous behavioral seizures, and epileptiform discharges in EEGs were not seen in these BACE1-deficient mice, in contrast to germline Bace1 knock-out mice or conditional knockouts in which Bace1 expression was abolished in forebrain excitatory neurons from an early age. However, like these other lines lacking BACE1, the BACE1-deficient mice described here show defects in axonal organization. (These axonal organization defects were also seen in a cohort of mice treated with tamoxifen from 6 to 9 months of age and examined at 2 years.)

No gender differences were observed.

Modification Details

Mice in which exon 2 of Bace 1 is flanked by LoxP sites (Ou-Yang et al., 2018) were crossed with R26CreER^T2mice (Ventura et al., 2007), which carry a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus.

Phenotype Characterization

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Paper Citations

1. Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med. 2018 Sep 19;10(459) PubMed.
2. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Feb 8;445(7128):661-5. Epub 2007 Jan 24 PubMed.

Other Citations

1. Robert Vassar

External Citations

1. The Jackson Laboratory Stock# 008463

Further Reading