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

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-beta (A beta) 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, A beta 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.