Research Models

Bace1 conditional knockout (Tesco)

Synonyms: Bace1 cKO, BACE1flox/flox;RosaCreERT2+/WT

Species: Mouse
Genes: Bace1
Modification: Bace1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6-Bace1tm1.1mrl
Genetic Background: C57BL/6N
Availability: BACE1flox/flox available through Taconic Model# 8263, Cryopreserved. RosaCreERT2 (R26-CreERT2) available through The Jackson Laboratory Stock# 008463, Live. 

Summary

This is the second of two similar models designed to mimic BACE1 inhibition, in which researchers can control the timing of BACE1 deficiency. These conditional knockouts avoid the developmental effects of BACE1 deficiency that are seen in germline knockouts, and, if crossed with mouse models of amyloidosis, allow the investigation of the effect of timing of BACE1 reduction on the progression of pathology.

Both lines 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 earlier model, 90 to 95 percent reductions in the levels of BACE1 were obtained in the cortices and hippocampi of year-old animals, following tamoxifen administration between 3 and 4 months. The current model (Lombardo et al., 2019) was created to achieve smaller decreases in BACE1 levels, in response to findings in clinical trials of BACE inhibitors: In humans, BACE inhibitors appeared to exacerbate memory deficits, prompting speculation that lower doses of drugs, resulting in less inhibition of enzyme activity, might provide benefits while avoiding drug-related cognitive decline (see Alzforum news story). While the earlier model is homozygous for the Cre transgene, the current model is hemizygous; the tamoxifen dosing regimens also differ between the models.

In the current model, tamoxifen was administered to mice between 8 and 12 weeks of age, and animals were evaluated at 4–5 months (“young”) or 12–14 months (“aged”). Tamoxifen-treated mice (hereafter, these mice are referred to as “BACE1-deficient mice”) were compared with vehicle-treated animals (hereafter, “controls”).

BACE1 levels in young BACE1-deficient mice were decreased by approximately 70 percent in cortex and 60 percent in hippocampus, relative to controls. The decrease in BACE1 was accompanied by an approximately 70 percent increase in cortical levels of full-length amyloid precursor protein (fl-APP) and decreases in the levels of APP C-terminal fragments (approximately 65 percent decrease) and Aβ40 (approximately 50 percent decrease).

In aged BACE1-deficient mice, there was an approximate 50 percent reduction in BACE1 levels in both cortex and hippocampus. Levels of cortical fl-APP, APP C-terminal fragments, and Aβ40 were affected to similar degrees as in young mice. In the hippocampus, levels of fl-APP in BACE1-deficient animals were increased by approximately 90 percent, while levels of APP C-terminal fragments and Aβ40 were approximately halved, compared with control mice.

Hypomyelination has been reported in germline Bace1 knockouts (Hu et al., 2006), so myelination was assessed in young and aged conditional knockouts. Myelination appeared normal in the peripheral nervous system (sciatic nerve) of these mice.

Abnormal organization of the hippocampal mossy fibers, thought to reflect axon-guidance defects, is seen in germline Bace1 knockouts and in the earlier conditional knockout model with >90 percent BACE1 reduction in the hippocampus (Ou-Yang et al., 2018). In the current model, aged mice do not show these mossy fiber abnormalities.

Aged BACE1-deficient mice display deficits in long-term potentiation at Shaffer collateral-CA1 synapses, compared with control mice.

Young and aged BACE1-deficient mice performed normally in a battery of behavioral tests, including tests of memory (spontaneous alternation in the Y-maze and contextual fear conditioning), sensory motor gating (pre-pulse inhibition), and anxiety (open field, light-dark transition task).

In the clinical trials in which BACE1 inhibitors were associated with poorer memory, levels of Aβ40 in the CSF were lowered by approximately 70 percent (Alzforum news story). CSF levels of Aβ40 have not yet been reported in this mouse model, nor has this model been studied in the context of amyloidosis.

Modification Details

Mice in which exon 2 of Bace1 is flanked by LoxP sites were crossed with R26-CreERT2 mice (Ventura et al., 2007), which carry a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus.

 

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Cognitive Impairment

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss

Plaques

No data.

Tangles

No data.

Neuronal Loss

No data.

Gliosis

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

Deficit in long-term potentiation at Schaffer collateral–CA1 synapses in slices from 14-month-old animals that had received tamoxifen between 8 and 12 weeks of age.

Cognitive Impairment

Animals that had received tamoxifen between 8 and 12 weeks of age were tested at 4–5 or 12–14 months. Tamoxifen-treated mice performed similarly to vehicle-treated controls in the Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition tests.

Last Updated: 17 Jan 2020

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Research Models Citations

  1. Bace1 conditional knock-out (adult, whole body) (Vassar)

News Citations

  1. Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors

Paper Citations

  1. . BACE1 partial deletion induces synaptic plasticity deficit in adult mice. Sci Rep. 2019 Dec 27;9(1):19877. PubMed.
  2. . Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.
  3. . Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med. 2018 Sep 19;10(459) PubMed.
  4. . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Feb 8;445(7128):661-5. Epub 2007 Jan 24 PubMed.

External Citations

  1. Taconic Model# 8263
  2. The Jackson Laboratory Stock# 008463

Further Reading

No Available Further Reading