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

Abstract

Background: preclinical, clinical, and epidemiological evidence support the notion that Alzheimer's disease (AD) is a multifactorial condition in which, along with β-amyloid (Aβ) and tau-related pathology, the synergistic activity of genetic, environmental, vascular, metabolic, and inflammatory factors promote the onset and progression of the disease. Epidemiological evidence indicate that glucose intolerance, deficits in insulin secretion or type 2 diabetes mellitus (T2DM) participate in increasing the risk of developing cognitive impairment or dementia. A pivotal role in the process is played by insulin 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 GLP-1R agonist, characterized by an extended half-life, 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 of brain aging and neurodegeneration.Methods: in this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. To that aim, we investigated the effects of 3-month exenatide treatment in 3xTg-AD mice challenged for six months with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, levels of Aβ and tau pathology as well as changes in cognitive performances.Findings and interpretation: results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD.

Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin‐4 treatment

“…Petrov et al (Petrov et al, 2015) showed that phosphorylated tau levels were not increased and alterations in cerebral amyloid levels did not play a critical role in memory loss of APP-PS1 transgenic mice when fed HFD from weaning for 6 months. More recently, consistent with our findings, a similar lack of elevated Aβ and phosphorylated tau levels in triple transgenic AD mice were found after 6 months of HFD in older mice and this was associated with no cognitive deficits (Bomba et al, 2019). Furthermore, our data are in agreement with the clinical data.…”

Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

“…Indeed, exenatide activates the transcription factor CREB with an increase of BDNF protein expression promoting the activation of neurotrophic pathway and inhibiting apoptosis in a mouse model of age-dependent cognitive dysfunction, potentiating long-term memory (Bomba et al, 2018). Even in a mouse model of AD (the 3xTg-AD undergoing high fat diet), exenatide reverted the impairment of BDNF signaling and neuroinflammation (Bomba et al, 2019).…”

Low Intensity Pulsed Ultrasound Prevents Recurrent Ischemic Stroke in a Cerebral Ischemia/Reperfusion Injury Mouse Model via Brain-derived Neurotrophic Factor Induction

“…BDNF is known to be a neurotrophic protective factor, involved in the regulation of several critical neuronal functions and neuroplasticity in patients who suffer nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke [35,36,37]. Several empirical studies have indicated the benefits of the increased expression of BDNF or receptor in different stages of stroke such as acute ischemic stroke, the rehabilitation process, and recurrence [37,38,39,40].…”