Exenatide Reverts the High-Fat-Diet-Induced Impairment of BDNF Signaling and Inflammatory Response in an Animal Model of Alzheimer’s Disease

Article type: Research Article

Authors: Bomba, Manuela^{a; b; 1} | Granzotto, Alberto^{a; b; 1} | Castelli, Vanessa^c | Onofrj, Marco^{a; b} | Lattanzio, Rossano^{a; d} | Cimini, Annamaria^{c; e; f} | Sensi, Stefano L.^{a; b; g; *}

Affiliations: [a] Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d’Annunzio of Chieti-Pescara, Italy | [b] Department of Neuroscience, Imaging, and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, Italy | [c] Department of Life, Health and Environmental Sciences, University of L’Aquila, Italy | [d] Department of Medical, Oral, and Biotechnological Sciences, University G. d’Annunzio of Chieti-Pescara, Italy | [e] Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA, USA | [f] National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy | [g] Departments of Neurology and Pharmacology, Institute for Mind Impairments and Neurological Disorders – iMIND, University of California – Irvine, Irvine, CA, USA

Correspondence: [*] Correspondence to: Prof. Stefano L. Sensi, Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d’Annunzio of Chieti-Pescara, Via Colle dell’Ara, Chieti 66100, Italy. Tel.: +39 0871 541544; Fax: +39 0871 541542; E-mail: ssensi@uci.edu.

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

Abstract: Alzheimer’s disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Keywords: Aging, BDNF, diabetes, exendin-4, insulin, insulin resistance, neurotrophic factors, dementia, T2DM

DOI: 10.3233/JAD-190237

Journal: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 793-810, 2019