Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals

M Bomba,S L Sensi,D Ciavardelli,C Di Ilio,A Consoli,M Piantelli,R Lattanzio,P Chiappini,L Mt Canzoniero,E Silvestri

doi:10.1038/cddis.2013.139

Abstract

Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.

Highlights

As examples of the commonalities between the two pathologies, recent studies indicate that Type 2 diabetes mellitus (T2DM), like Alzheimer’s disease (AD), produces a variety of neurochemical, neuroanatomical, and behavioral changes that can be linked to acceleration of brain aging,[3] increased oxidative stress,[4,5] and neuroendocrine alterations.[6]
In order to verify whether the drug has the same effects in our animal models, we investigated changes in body weight of treated and untreated presenilin-1 knock-in (PS1-KI) and triple transgenic mouse carrying AD-linked mutations (3xTg-AD) mice
It should be noted that 7-month-old 3xTg-AD mice gained statistically significant more weight compared with PS1-KI mice, a phenomenon that is independent of drug treatment as indicated by three-factor ANOVA showing significant effect of genotype (Figure 1; P 1⁄4 2 Â 10 À 9)

Summary

Introduction

As examples of the commonalities between the two pathologies, recent studies indicate that T2DM, like AD, produces a variety of neurochemical, neuroanatomical, and behavioral changes that can be linked to acceleration of brain aging,[3] increased oxidative stress,[4,5] and neuroendocrine alterations.[6]. Glucagon like peptide-1 (GLP-1) is an incretin hormone[11] that controls insulin and glucose homeostasis.[12] Binding of GLP-1 to its receptor (GLP-1R) is coupled with multiple signal transduction pathways that lead to the activation of adenylyl cyclase, protein kinase c (PKC) and mitogen activated protein (MAP) kinase.[13] GLP-1R agonists act on b-cells to stimulate insulin secretion and increase glucose-dependent insulin release. These drugs are successfully employed for T2DM treatment. Exenatide has been proposed as a therapeutic agent in neurological conditions like Parkinson’s disease (PD) and Alzheimer’s disease (AD).[17,18]

Methods

Results

Discussion

Conclusion