Genes: Bace1, APP, PSEN1
Mutations: APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: Bace1: Conditional Knock-out; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Bace1fl/fl not yet available. UBC-Cre-ERT2 available from The Jackson Laboratory, Stock# 007001. 5xFAD available from The Jackson Laboratory, JAX MMRRC Stock# 034848.
These transgenic mice were designed to mimic BACE1 inhibition in the context of amyloid pathology, while avoiding the developmental effects of Bace1 deficiency that are seen in germline knockouts. Mice are hemizygous for human APP and PSEN1 transgenes with a total of five AD-linked mutations (5xFAD), homozygous for a floxed Bace1 gene, and hemizygous for a transgene encoding Cre recombinase fused to a modified human estrogen receptor. Due to leakiness of the transgene, treatment with the estrogen receptor modulator tamoxifen is not required for Cre expression, and these mice show an age-dependent decline in BACE1 levels beginning around the time of weaning. (Hereafter, these mice are referred to as “5xFAD/BACE1 KO.”) While amyloid plaques accumulate aggressively in 5xFAD mice with normal Bace1 expression, plaques accumulate more slowly and eventually disappear from the brains of 5xFAD/BACE1 KO mice. Bace1 deletion also ameliorates deficits in long-term potentiation and cognition that are seen in 5xFAD mice.
Unless stated otherwise, this description refers to comparisons between 5xFAD/BACE1 KO mice and 5xFAD mice homozygous for floxed Bace1 but without the Cre recombinase transgene (hereafter, “control 5xFAD”).
BACE1 levels in the brains of 5xFAD/BACE1 KO mice were reduced by approximately 40 percent at day 30, and the enzyme was barely detectable at day 300.
At day 75, the number of amyloid plaques in cortex and hippocampus did not differ between the two genotypes. Between days 75 and 120, plaques accumulated at a much slower rate in the 5xFAD/BACE1 KO mice than in control 5xFAD mice (at day 120, there were 63 percent fewer plaques in 5xFAD/BACE1 KO brains). Then, as plaque numbers continued to increase with age in the control 5xFAD animals, the numbers fell in the mice lacking BACE1, until, at day 300, no plaques were seen in the BACE1-deficient mice. Levels of detergent-insoluble Aβ40 and Aβ42, measured in the hippocampus, followed a pattern similar to plaque deposition.
Gliosis also followed similar patterns as plaque deposition. Microgliosis and astrogliosis, assessed by Iba1 and Smi22 immunoreactivity, respectively, increased in both genotypes between days 75 and 120, with the immunoreactivity for both markers being less in the BACE-deficient animals. While gliosis continued to increase in control 5xFAD brains, it was barely detectable at 300 days in 5xFAD/BACE1 KO brains. The accumulation of dystrophic neurites also followed this pattern.
Long-term potentiation at Schaffer collateral–CA1 synapses was essentially abolished in slices obtained from 10- to 12-month-old control 5xFAD mice, while this deficit was partially rescued in slices from 5xFAD/BACE1 KO animals.
Control 5xFAD mice showed deficits in contextual fear conditioning at 8 to 10 months of age, and this deficit, too, was rescued by BACE1 deletion.
5xFAD mice were first crossed with Bace1fl/fl mice in which exon 2 of the mouse Bace1 gene is flanked by loxP sites (Hu et al., 2018) to generate 5xFAD mice homozygous for a floxed Bace1 gene (BACE1fl/fl/5xFAD). Bace1fl/fl mice were also crossed with UBC-Cre-ERT2 mice (The Jackson Laboratory, Stock# 007001) to obtain BACE1fl/fl/UbcCreER mice. BACE1fl/fl/5xFAD mice were then bred to BACE1fl/fl/UbcCreER mice. All lines were backcrossed with C57BL/6J mice for at least five generations.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Impairment
- Neuronal Loss
- Synaptic Loss
Accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.
Reactive astrocytes and microglia accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.
Changes in LTP/LTD
Deficit in LTP at Schaffer collateral–CA1 synapses, but less severe than in control 5xFAD mice.
Cued and contextual fear conditioning normal, tested at eight to 10 months of age.
Last Updated: 18 Jan 2019
Research Models Citations
- Hu X, Das B, Hou H, He W, Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med. 2018 Mar 5;215(3):927-940. Epub 2018 Feb 14 PubMed.