Is the Urea Cycle Involved in Alzheimer's Disease?

Article type: Research Article

Authors: Hansmannel, Franck^{a; b; c} | Sillaire, Adeline^{a; b; c} | Kamboh, M. Ilyas^d | Lendon, Corinne^e | Pasquier, Florence^{c; f} | Hannequin, Didier^g | Laumet, Geoffroy^{a; b; c} | Mounier, Anais^{a; b; c} | Ayral, Anne-Marie^{a; b; c} | DeKosky, Steven T.^h | Hauw, Jean-Jacquesⁱ | Berr, Claudine^j | Mann, David^k | Amouyel, Philippe^{a; b; c; f} | Campion, Dominique^g | Lambert, Jean-Charles^{a; b; c; *}

Affiliations: [a] INSERM U744, Lille, France | [b] Institut Pasteur de Lille, Lille, France | [c] Université de Lille Nord de France, Lille, France | [d] Department of Human Genetics and Alzheimer's Disease Research Centre, University of Pittsburgh, USA | [e] Molecular Psychiatry Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, Australia | [f] CHRU de Lille, Lille, France | [g] INSERM U614, Faculté de Médecine-Pharmacie de Rouen, Rouen, France | [h] University of Virginia School of Medicine, Charlottesville, VA, USA | [i] APHP Laboratoire de Neuropathologie GH Pitié-Salpêtrière, Inserm UMR-S 975, CNRS UMR 7225, UPMC Paris VI UMR 7225, S-975, Centre de Recherche de l'Institut Cerveau-Moelle, Paris, France | [j] INSERM U888; Université Montpellier 1, Hôpital La Colombière, Montpellier, France | [k] Greater Manchester Neuroscience Centre, University of Manchester, Manchester, UK

Correspondence: [*] Correspondence to: Jean-Charles Lambert, Unité INSERM 744, Institut Pasteur de Lille, BP 245, 1, rue de professeur Calmette, F-59019 Lille cedex, France. Tel.: +33 (0)3 20 87 73 91; Fax: +33 (0)3 20 87 78 94; E-mail: jean-charles.lambert@pasteur-lille.fr.

Abstract: Since previous observations indicated that the urea cycle may have a role in the Alzheimer's disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age-at-onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.

Keywords: Alzheimer's disease, ammonium, arginase, association study, citrulline NO cycle, nitric oxide, polyamines, urea cycle

DOI: 10.3233/JAD-2010-100630

Journal: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 1013-1021, 2010