Deciphering the genetic interaction between klotho and APOE with novel mouse models. (20th December 2022)

• Record Type: Journal Article
• Authors: Carter, Gregory W; Preuss, Christoph; Garceau, Dylan; Kotredes, Kevin P; Sasner, Michael
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.064175
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Apolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for LOAD, but APOE4 carriers do not always develop LOAD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klotho harbors two common missense variants ( rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models. Methods: We introduced the human klotho variants into the mouse. Mouse klotho differs at the key amino acid position p.C370S rendering the native mouse haplotype as "KL‐F/S", matching neither of the observed human haplotypes. We have replaced this native haplotype with the homozygous protective KL‐V/S and common KL‐F/C haplotypes using CRISPR/Cas9. To validate the effects of these klotho haplotypes on klotho secretion, soluble p‐KL serum levels of four month old mice were compared after cheek bleeding using ELISA. We also measured p‐KL in eight month old amyloidogenic App SAA mutant mice, which have amyloid plaques in the brain. Results: Genomic modifications in mouse klotho were confirmed by PCR and Sanger sequencing. Secreted p‐KL was decreased in KL‐F/C mice harboring the novel mouse risk haplotype when compared to age matched B6 controls and KL‐V/S mice. In contrast, KL‐V/S mice showed no significant differences in soluble p‐KL serum levels when compared to B6 controls. Secreted p‐KL levels in KL‐V/S mice were significantly elevated when compared to the App SAA mice, whereas young KL‐F/C mice showed similar levels to the aged App SAA model. Conclusions: Taken together, these data suggest the native mouse klotho allele may acts similarly to the protective KL‐V/S haplotype, while the KL‐F/C haplotype leads to lower secreted klotho and potentially greater disease risk. These models are therefore suitable for experiments to elucidate how klotho variants protect from LOAD pathologies, and will enable detailed studies of how this protection is specific to the APOE4 genotype.