Rs5848 Variant Influences GRN mRNA Levels in Brain and Peripheral Mononuclear Cells in Patients with Alzheimer's Disease

Article type: Research Article

Authors: Fenoglio, Chiara^{a; *} | Galimberti, Daniela^a | Cortini, Francesca^a | Kauwe, John S.K.^b | Cruchaga, Carlos^b | Venturelli, Eliana^a | Villa, Chiara^a | Serpente, Maria^a | Scalabrini, Diego^a | Mayo, Kevin^b | Piccio, Laura M.^{a; c} | Clerici, Francesca^d | Albani, Diego^e | Mariani, Claudio^d | Forloni, Gianluigi^e | Bresolin, Nereo^a | Goate, Alison M.^b | Scarpini, Elio^a

Affiliations: [a] Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy | [b] Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA | [c] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA | [d] Center for Research and Treatment on Cognitive Dysfunctions, University of Milan, “Luigi Sacco” Hospital, Milan, Italy | [e] Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

Correspondence: [*] Corresponding author: Chiara Fenoglio, Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. Tel.: +39 2 5033887; Fax: +39 2 50320430; E-mail: [email protected].

Abstract: Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 ± 0.07 versus 1.73 ± 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 ± 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 ± 0.23 versus 0.70 ± 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 ± 0.14, CC = 1.22 ± 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival.

Keywords: Alzheimer's disease (AD), cerebrospinal fluid (CSF), peripheral mononuclear cells (PBMC), progranulin (GRN), single nucleotide polymorphism (SNP)

DOI: 10.3233/JAD-2009-1170

Journal: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 603-612, 2009