Expression of the Ghrelin and Neurotensin Systems is Altered in the Temporal Lobe of Alzheimer's Disease Patients

Article type: Research Article

Authors: Gahete, Manuel D.^a | Rubio, Alicia^b | Córdoba-Chacón, José^a | Gracia-Navarro, Francisco^a | Kineman, Rhonda D.^{c; d} | Avila, Jesús^b | Luque, Raúl M.^{a; 1} | Castaño, Justo P.^{a; 1; *}

Affiliations: [a] Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain | [b] Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid (CSIC/UAM), and CIBER Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain | [c] Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA | [d] Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA

Correspondence: [*] Correspondence to: Dr. Justo P. Castaño and Dr. Raúl M. Luque, Department of Cell Biology, Physiology and Immunology, Campus Universitario de Rabanales, Edificio Severo Ochoa (C6), Planta 3, University of Córdoba, E-14014 Córdoba, Spain. Tel.: +34 957 21 85 94; Fax: +34 957 21 86 34; E-mail: [email protected], [email protected].

Note: [1] Raúl M. Luque and Justo P. Castaño co-directed this work.

Note: [] Handling Associate Editor: Garth Bissette

Abstract: Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer's disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS-R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology.

Keywords: Alzheimer's disease, brain temporal lobe, ghrelin, GHS-R, In2-ghrelin variant, neurotensin, NTSR

DOI: 10.3233/JAD-2010-100873

Journal: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 819-828, 2010