Modification: Bace1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: BACE1fl/fl available through Robert Vassar; CamKIIα-iCre available through the European Mouse Mutant Archive (EMMA) ID# EM: 01153, cryopreserved, sperm
In these conditional knock-out mice, Bace1 expression is eliminated in forebrain excitatory neurons beginning during the first postnatal week. These mice were generated by crossing mice with a floxed Bace1 gene to mice carrying a transgene encoding Cre recombinase driven by the CamKIIα promoter (hereafter, these crosses 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 (hereafter “control”). Survival rates are similar in BACE1-deficient mice and control mice. While BACE1-deficient mice are smaller than controls at younger ages, body weights of the two genotypes are similar by 3 months. No gender differences are observed.
By four days of age BACE1 protein is no longer detectable in the forebrains of BACE1-deficient mice. Loss of BACE1 is accompanied by the accumulation of full-length BACE1 substrates (APP, CHL1, Sez6) and reduced levels of cleavage products BACE1 (cleaved CHL1, NRG1, Sez6, and APP β-CTF).
Hypomyelination and defects in axon organization were observed in BACE1-deficient mice, similar to what has been reported in mice with germline knock out of Bace1.
BACE1-deficient mice showed delayed learning, but normal memory, in the Morris water maze at 6 and 9 months of age. Alternation in the Y-maze test of working memory and cued- and contextual- fear conditioning were also normal. However, BACE1-deficient mice exhibited hyperactivity when placed in novel environments.
Spontaneous behavioral seizures and abnormal EEGs (epileptiform discharges) were seen in BACE1-deficient mice, although electrographic seizure activity is not as severe as in mice with germline knockout of Bace1.
Mice in which exon 2 of Bace1 is flanked by LoxP sites (BACE1fl/fl) were crossed with mice carrying a transgene encoding Cre recombinase driven by the CamKIIα promoter (Casanova et al., 2001).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Changes in LTP/LTD
Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning.
Last Updated: 22 Feb 2019
- Casanova E, Fehsenfeld S, Mantamadiotis T, Lemberger T, Greiner E, Stewart AF, Schütz G. A CamKIIalpha iCre BAC allows brain-specific gene inactivation. Genesis. 2001 Sep;31(1):37-42. PubMed.