B6.129(Cg)-Becn1^tm2.1Blev/J

Stock number: 033360
Product name: Becn1^F121A , Becn1^FA
Research areas: Cell Biology Research, Neurobiology Research

Description

Becn1^F121A knock-in mice express an F121A point mutation in the Becn1 (beclin 1) gene that inhibits BCL2 (B cell leukemia/lymphoma 2) protein interactions. Homozygotes exhibit hyperactivated autophagy that significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in mouse models of Alzheimer's Disease (AD).

Detailed description

Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD). Beclin 1, encoded by the Becn1 gene, plays a central role in autophagy regulation and is involved in early embryonic development, tumorigenesis, tumor progression and neurodegeneration.

These Becn1^F121A knock-in mice express an F121A point mutation in the Becn1 gene that inhibits BCL2 (B cell leukemia/lymphoma 2) protein interactions. Homozygotes exhibit hyperactivated autophagy that significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in mouse models of Alzheimer's Disease. Becn1^F121A decreases amyloid accumulation and improves cognitive function in the 5XFAD Alzheimer's mouse model (see Stock No. 008730), which overexpress a combination of 5 familial Alzheimer's disease (FAD) mutations in human APP (amyloid beta (A4) precursor protein) and human PSEN1 (presenilin 1) proteins and show early amyloid deposition beginning at 2 months of age and cognitive decline at 6 months of age. Homozygous expression of the Becn1^F121A mutation decreases mortality in PDAPP (Tg(APPV717F)109Ili) mice carrying the V717F (Indiana) mutation in APP.

Constitutively-active autophagy occurs even under non-autophagy-inducing conditions in multiple tissues, including the brain. Autophagic vesicles from these mice have been found to incorporate amyloid β peptide (Aβ) oligomers, a major cause of Alzheimer's disease, thus providing evidence that oligomerized amyloids are substrates of autophagy.

For unknown reasons, heterozygote x heterozygote crosses have been found to yield fewer than predicted wildtype progeny (July, 2023).

Development

Becn1 genomic DNA, derived from a BAC clones RP23-281C18 and RP23-286N22, was modified such that F121 (TTT) in exon 6 was replaced by A (GCT). A neomycin resistance marker flanked by loxP sites was inserted between exons 7 and 8. The resulting targeting construct was linearized and electroporated into 129SvEv-derived embryonic stem (ES) cells. Resultant mice were crossed with germline CAG-cre recombinase-expressing mice on a C57BL/6J background to remove the neomycin cassette. This strain was backcrossed to C57BL/6J for more than 15 generations by the donating laboratory.

Allele

Symbol: Becn1^tm2.1Blev
Name: targeted mutation 2.1, Beth Levine
MGI accession ID: MGI:6156896
Generation method: Targeted
Attributes: Constitutively active
Synonyms: Becn1^F121A; Becn1^FA; Becn1^tm1.1Hec
Marker symbol: Becn1
Marker name: beclin 1, autophagy related
Marker synonyms: Atg6; beclin1; MGC:6843; VPS30
Chromosome: 11
Strain of origin: 129
Molecular note: A floxed neo cassette was inserted in intron 7 and an F121A mutation was created in exon 6 via homologous recombination. Cre-meditated recombination removed the neo cassette. The mutation in exon 6 disrupts binding to BCL2 resulting in constitutively high autophagy.