Klotho Gene Expression Is Decreased in Peripheral Blood Mononuclear Cells in Patients with Alzheimer’s Disease and Frontotemporal Dementia

Article type: Research Article

Authors: Sorrentino, Federica^{a; 1} | Fenoglio, Chiara^{a; b; 1; *} | Sacchi, Luca^a | Serpente, Maria^b | Arighi, Andrea^b | Carandini, Tiziana^b | Arosio, Beatrice^a | Ferri, Evelyn^b | Arcaro, Marina^b | Visconte, Caterina^a | Rotondo, Emanuela^b | Scarpini, Elio^b | Galimberti, Daniela^{a; b}

Affiliations: [a] University of Milan, Milan, Italy | [b] Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

Correspondence: [*] Correspondence to: Chiara Fenoglio, University of Milan, Milan, Italy. Tel.: +39 0255033858; E-mail: chiara.fenoglio@unimi.it.

Note: [1] These authors contributed equally to this work.

Abstract: Background:The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer’s disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. Objective:To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. Methods:A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. Results:KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation – 4.286 and – 6.561 versus controls in AD and FTD, respectively, p = 0.0037). Conclusion:This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.

Keywords: Alzheimer’s disease, expression, frontotemporal dementia, Klotho, neurodegeneration

DOI: 10.3233/JAD-230322

Journal: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1225-1231, 2023