The therapeutic potential of glucagon-like peptide-1 analogs in the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) affects more than 25% of individuals over 80 years of age and its prevalence is expected to rise with the increase of life expectancy. Existing drugs only provide symptomatic benefits but there are no currently available diseasemodifying therapies. However, evidence from preclinical studies indicates that several drugs approved for other indications could have beneficial effects on Alzheimer’s pathology, and some of them are currently being evaluated in clinical trials [1]. In the last decades an increase in the incidence of both type 2 diabetes (T2D) and neurodegenerative disorders has been observed, posing a significant health and social challenge due to increased morbidity and mortality. T2D increases the risk of AD and there is an increased incidence of T2D in AD patients [2], probably due to common pathophysiological mechanisms shared between these diseases, and one that can be identified is insulin desensitization. Indeed, in AD brain, insulin signaling is desensitized, showing a molecular profile similar to that found in peripheral tissues of diabetic subjects [3]. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with several effects on glycemic homeostasis, stimulating insulin and decreasing glucagon secretion. Currently, the GLP-1 receptor agonists exendin-4, liraglutide and lixisenatide are approved for treatment of T2D [4]. Besides its metabolic effects, GLP-1 has also been shown to act as a growth factor in the brain, inducing neurite growth and protecting against oxidative injury; GLP-1 receptor knock-out mice present with impaired hippocampal long-term potentiation of synaptic transmission [5]. The GLP-1 receptor is found in neurons throughout the nervous system, is maintained during aging and disease, and GLP-1 and its analogs effectively cross the blood–brain barrier. In the context of AD-related brain amyloid pathology, the preclinical results of GLP-1 analogs have shown promising potential. Exendin-4 has been shown to reduce endogenous levels of β-amyloid in the mouse brain [6]. Liraglutide has also been shown to protect synapses from the detrimental effects of amyloid [7,8] and it was able to significantly reduce the β-amyloid plaque load and the total amount of β-amyloid in the brain of a transgenic mouse model of AD. Importantly, in a late-stage animal model of AD, liraglutide demonstrated restorative effects in both brain structure and function, reducing both β-amyloid plaques and soluble amyloid oligomers [9], suggesting that liraglutide could potentially influence the amyloid production. Moreover, GLP-1 analogs have been demonstrated to promote cell proliferation in the rat hippocampus and increase the number of neuronal progenitor cells in mouse models of diabetes. GLP-1R activators induce the differentiation of neuronal stem cell and stimulate neurite outgrowth in a manner similar to nerve “…preclinical evidence strongly supports the hypothesis that GLP-1 analogs can represent promising candidates for Alzheimer’s disease treatment.”