Species: Mouse
Genes: SORL1
Modification: SORL1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Rosa26^TgSORL1WT
Genetic Background: C57BL/6J
Availability: Available through Thomas Willnow.

This mouse model enables Cre-inducible overexpression of human SORL1. A transgene containing SORL1 cDNA downstream of the cytomegalovirus early enhancer/chicken β-actin promoter and a floxed neomycin resistance cassette with a polyA stop element (neo-R) was introduced into the murine Rosa26 locus (mice carrying this transgene are referred to as Rosa26^TgSORL1WT). Cre-mediated excision of neo-R induces SORL1 overexpression.

Tissue-specific or temporal control of human SORL1 expression can be achieved through the selection of the Cre-expressing line to cross with the SORL1 carriers. In the initial report of this model, SORL1 transgenic mice were crossed with Cre deleter mice, in which the Cre transgene is inserted into the Rosa26 locus and is expected to be expressed ubiquitously (Caglayan et al., 2014).

Hereafter, Cre-expressing mice heterozygous for the SORL1 transgene will be referred to as Rosa26^Tg/+, and mice homozygous for the SORL1 transgene will be called Rosa26^Tg/Tg.

Rosa26^Tg/+ mice are viable and fertile and do not exhibit any obvious pathological phenotypes (Caglayan et al., 2014). However, approximately half of the Rosa26^Tg/Tg mice die shortly after birth.

Levels of SORLA protein (human and mouse) in the hippocampi and cortices of Rosa26^Tg/+ mice are about fourfold those of endogenous murine SORLA in control mice. In order to examine the expression of human SORLA at the cellular level in the brain, Rosa26^Tg/+ mice were crossed with SORLA-deficient mice lacking full-length murine SORLA. Human SORLA was seen only in neurons, a somewhat surprising finding given that the cytomegalovirus early enhancer/chicken β-actin promoter is expected to be ubiquitously active (Caglayan et al., 2014).

APP metabolites | LTP | Behavior | Transcriptomics | Other | Modification Details | Related Strains

APP metabolites

Levels of Aβ40 and Aβ42 were two- to threefold lower in the brains of newborn Rosa26^Tg/+ and Rosa26^Tg/Tg mice, compared with control mice expressing only endogenous SORLA (Caglayan et al., 2014).

SORLA-transgenic mice were crossed with PDAPP mice, a model of amyloidosis, to examine the effects of overexpression of human SORLA on human APP metabolites. Levels of Aβ40 and Aβ42 were decreased in brain lysates from mice expressing human SORLA, compared with PDAPP mice expressing only the murine receptor; levels of sAPPs or CTFs did not differ between genotypes. However, levels of Aβ40 in the interstitial fluid, collected by microdialysis in the hippocampus, did not differ between genotypes, implying that SORLA overexpression primarily affected intracellular Aβ (Caglayan et al., 2014).

LTP

Long-term potentiation at Schaffer collateral-CA synapses was similar in hippocampal slices from 3-month-old Rosa26^Tg/+ and wild-type mice (Huang et al., 2017). However, while the application of Aβ oligomers impaired LTP in slices from wild-type mice, these oligomers did not affect LTP in SORLA transgenic mice.

Behavior

Rosa26^Tg/+ SORLA transgenic mice performed similarly to wild-type mice in the acquisition and retention phases of the Morris Water Maze, when tested at 3 months of age (Huang et al., 2017). However, as seen with LTP, the SORL1 transgenic mice were insensitive to the application of Aβ oligomers: While hippocampal injection of Aβ oligomers prevented wild-type mice from learning the location of the escape platform, Aβ oligomers did not affect the performance of the SORL1 transgenic mice (Huang et al., 2017).

Transcriptomics

RNA-Seq on hippocampi revealed approximately 1,400 genes (449 upregulated, 930 downregulated) that were differentially regulated in SORL1 transgenic versus wild-type mice (Stupack et al., 2020). Bioinformatic analyses showed that these genes are related to RAS and MAPK signaling, focal adhesion, and axon guidance, growth, and regeneration.

Other

SORLA has been shown to interact with the receptor tyrosine kinase EphA4. Less phosphorylated (activated) EphA4 was found in the hippocampi of Rosa26^Tg/+ SORL1 transgenic mice, compared with wild-type mice. Aβ oligomers injected into the hippocampi of wild-type mice increased EphA4 activation but did not affect EphA4 in SORL1 transgenic animals (Huang et al., 2017).

Neurons cultured from SORL1 transgenic mice were found to have longer neurites, including longer axons, than neurons from wild-type mice (Stupack et al., 2020).

The phosphoprotein profile in the cortex differed between 3-month-old SORL1 transgenic mice and wild-type mice: More than 1,400 phosphopeptides were differentially expressed in the two genotypes, including components of the RAS and MAPK and EGFR/ErbB pathways, and pathways regulating the actin cytoskeleton and endocytosis (Stupack et al., 2020).

Modification Details

SORL1 cDNA downstream of the cytomegalovirus early enhancer/chicken β-actin promoter and a floxed neomycin resistance cassette with a polyA stop element (neo-R) was introduced into the murine Rosa26 locus. Cre-mediated excision of neo-R induces SORL1 overexpression.

Related Strains

Rosa26^{TgSORL1WTTg(Adipoq-Cre)1Evdr/J}. As noted above, choice of the Cre-expressing line allows tissue-specific control of expression of the human SORL1 transgene. Rosa26^TgSORL1WT mice were crossed with mice that express Cre only in adipocytes (Tg^{(Adipoq-Cre)1Evdr/J}). Human SORLA was expressed in adipose tissues, but not in hypothalamus, liver, or muscle in the offspring of these crosses. Studies of these animals revealed a SORL1 gene-dose effect on obesity and glucose tolerance (Schmidt et al., 2016).

Phenotype Characterization

COMMENTS / QUESTIONS

1. • Frédéric Checler
     Institut de Pharmacologie Moléculaire et Cellulaire
   • Posted: 14 Feb 2014
   • Paper: Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation.

   This is an important paper. It appears as one of very few examples of delineated risk factors for AD for which a plausible function linked to Aβ degradation is clearly documented. Of most interest, obviously, is the observation that an AD-linked mutation could directly impair the Aβ-SORLA interaction and lead to enhanced Aβ levels, thereby bringing a biological rational for the original genetic observation. This adds a bit more support to the amyloid cascade hypothesis. In sporadic AD, there are no clues of enhanced Aβ formation. Rather, it is the decrease of degradation rates that leads to increased cerebral loads of peptides.

   This paper further supports the view that Aβ levels are modulated downstream of secretase actions. Both SORLA levels that are diminished in sporadic AD-affected brains and mechanisms of action of SORLA support the view that this receptor contributes to sporadic AD. The fact that the mutation the authors examined, located in the SORLA domain that interacts with Aβ, affects SORLA function is interesting. The question to address is whether other SORLA mutations located outside this VPS10P domain trigger the same effect. It is possible that mutations outside the binding domain could alter the 3-D structure to ultimately affect lysosomal Aβ degradation. Alternatively, it remains possible that additional AD-linked mutations enhance AD risk by affecting other pathways, even unrelated to APP trafficking/processing.

   View all comments by Frédéric Checler

Make a comment or submit a question

To make a comment you must login or register.

References

Research Models Citations

1. PDAPP(line109)

Paper Citations

1. Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, Kitago Y, Füchtbauer EM, Füchtbauer A, Holtzman DM, Takagi J, Willnow TE. Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci Transl Med. 2014 Feb 12;6(223):223ra20. PubMed.
2. Huang TY, Zhao Y, Jiang LL, Li X, Liu Y, Sun Y, Piña-Crespo JC, Zhu B, Masliah E, Willnow TE, Pasquale EB, Xu H. SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration. J Exp Med. 2017 Dec 4;214(12):3669-3685. Epub 2017 Nov 7 PubMed.
3. Stupack J, Xiong XP, Jiang LL, Zhang T, Zhou L, Campos A, Ranscht B, Mobley W, Pasquale EB, Xu H, Huang TY. Soluble SORLA Enhances Neurite Outgrowth and Regeneration through Activation of the EGF Receptor/ERK Signaling Axis. J Neurosci. 2020 Jul 29;40(31):5908-5921. Epub 2020 Jun 29 PubMed.
4. Schmidt V, Schulz N, Yan X, Schürmann A, Kempa S, Kern M, Blüher M, Poy MN, Olivecrona G, Willnow TE. SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity. J Clin Invest. 2016 Jul 1;126(7):2706-20. Epub 2016 Jun 20 PubMed.

Other Citations

1. Thomas Willnow

External Citations

1. Cre deleter

Further Reading