Species: Mouse
Genes: Sorl1
Modification: Sorl1: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Generated on a mixed 129SvEmcTer X C57BL/6N genetic background, subsequently backcrossed to C57BL/6J.
Availability: Available through Thomas Willnow.

In this model of SORLA deficiency, the 5' region of exon 4 of the murine Sorl1 gene was replaced by a neomycin resistance cassette. Although mice homozygous for the disrupted allele do not make full-length SORLA protein (Andersen et al., 2005), an incomplete form of the receptor has been detected at low levels in the brains of these animals (Dodson et al., 2008). Sorl1 mRNA from the disrupted allele is 162 base pairs smaller than wild-type message, and the protein is missing 54 amino acids within the N-terminal region of the VPS10P domain. Levels of the incomplete protein are at least fourfold lower than levels of the full-length protein expressed in wild-type mice. Heterozygous animals generate both full-length and incomplete forms of SORLA.

SORLA-deficient mice are viable and fertile (Andersen et al., 2005). Some physiological abnormalities have been noted in mice homozygous for the disrupted gene, including deficits in salt homeostasis accompanied by lower mean arterial blood pressure (Reiche et al., 2010), and differences in body composition—decreased fat and increased lean body mass—compared with littermate controls (Schmidt et al., 2016). In addition, SORLA-deficient mice were found to have fewer cells in the inner nuclear layer of the retina than wild-type mice (Monti et al., 2020), but it is not known whether this retinal abnormality affects the animals’ vision.

Amyloidosis

Levels of APP and its metabolites were measured in extracts of cerebral cortices from 10-month-old mice. While APP levels did not differ between SORLA-deficient mice and wild-type controls, levels of sAPP and Aβ were elevated—the amounts of both Aβ40 and Aβ42 were about 30 percent higher in the mice with the disrupted Sorl1 allele (Andersen et al., 2005). Amyloid plaques were not seen in the brains of either genotype.

Subsequently, the levels of mature (glycosylated) APP, measured at 6 months of age, were found to be reduced in the hippocampi of SORLA-deficient mice (Rohe et al., 2008).

When SORLA-deficient mice were crossed with the APPswe/PS1ΔE9 model of amyloidosis, levels of APP metabolites were altered—sAPPα and sAPPβ were elevated, while APP CTFs were decreased—and amyloid deposition was accelerated, compared with the parental APPswe/PS1ΔE9 line (Dodson et al., 2008).

Findings from crosses of SORLA-deficient mice with PDAPP mice, another model of amyloidosis, confirmed that SORLA depletion results in increased APP catabolism: Levels of sAPPα, sAPPβ, and Aβ were significantly elevated in primary hippocampal neurons derived from PDAPP mice lacking SORLA, compared with neurons derived from the parental PDAPP line.  Also, amyloid deposition was accelerated, and levels of detergent-insoluble Aβ were elevated, in the brains of 10-month-old PDAPP;Sorl1^-/- mice, compared with littermates heterozygous for the Sorl1 deletion (Rohe et al., 2008).

Behavior

Compared with wild-type mice, 3- to 4-month-old SORLA-deficient mice exhibited more arm entries and more time spent in the open arms of the elevated plus maze—behaviors interpreted as evidence of hyperactivity and reduced anxiety—and were insensitive to amphetamine (Glerup et al., 2013). Hyperactivity was also noticed in the open field test.

Other

SORLA-deficient mice exhibited increased neuronal ERK signaling and enhanced adult neurogenesis; these effects of SORLA deficiency were APP-dependent, possibly stimulated by elevated sAPP in the Sorl1 knockout mice (Rohe et al., 2008).

Early data suggest that nigrostriatal connectivity is disrupted in SORLA-deficient mice: Approximately 25 percent fewer dopaminergic neurons project from the substantia nigra to the striatum in the knockout mice compared with wild-type mice, assessed at 10 weeks of age (Glerup et al., 2013).

Modification Details

The 5' region of exon 4 of the murine Sorl1 gene was replaced by a neomycin resistance cassette, through homologous recombination.

Phenotype Characterization

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References

Research Models Citations

1. APPswe/PSEN1dE9 (line 85)
2. PDAPP(line109)

Paper Citations

1. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. PubMed.
2. Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J, Levey AI, Willnow TE, Lah JJ. Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. J Neurosci. 2008 Nov 26;28(48):12877-86. PubMed.
3. Reiche J, Theilig F, Rafiqi FH, Carlo AS, Militz D, Mutig K, Todiras M, Christensen EI, Ellison DH, Bader M, Nykjaer A, Bachmann S, Alessi D, Willnow TE. SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na(+)-K(+)-Cl(-) cotransporter 2. Mol Cell Biol. 2010 Jun;30(12):3027-37. Epub 2010 Apr 12 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.
5. Monti G, Jensen ML, Mehmedbasic A, Jørgensen MM, Holm IE, Barkholt P, Zole E, Vægter CB, Vorum H, Nyengaard JR, Andersen OM. SORLA Expression in Synaptic Plexiform Layers of Mouse Retina. Mol Neurobiol. 2020 Jul;57(7):3106-3117. Epub 2020 May 29 PubMed.
6. Rohe M, Carlo AS, Breyhan H, Sporbert A, Militz D, Schmidt V, Wozny C, Harmeier A, Erdmann B, Bales KR, Wolf S, Kempermann G, Paul SM, Schmitz D, Bayer TA, Willnow TE, Andersen OM. Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem. 2008 May 23;283(21):14826-34. PubMed.
7. Glerup S, Lume M, Olsen D, Nyengaard JR, Vaegter CB, Gustafsen C, Christensen EI, Kjolby M, Hay-Schmidt A, Bender D, Madsen P, Saarma M, Nykjaer A, Petersen CM. SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET. Cell Rep. 2013 Jan 31;3(1):186-99. Epub 2013 Jan 17 PubMed.

Other Citations

1. Thomas Willnow

Further Reading