The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

Abstract

Currently, there is no disease-modifying treatment available for Alzheimer’s and Parkinson’s disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca2+ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD.

Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond

“…It showed that liraglutide treated patients performed significantly better than placebo in temporal lobe and whole cortical magnetic resonance imaging volume and cognitive function [77] [78,79]. An in-depth review on the pathophysiology, animal studies and clinical trials of the neuroprotective mechanisms of GLP-1RAs was recently published [80].…”

Neuroprotective Properties of Peptides

“…The NTS neurons create proglucagon and/ or GLP-1-positive projections that are directed into the olfactory bulb, several hypothalamic nuclei, the bed nucleus of the stria terminalis, the lateral and medial septal nuclei, the amygdaloid complex, the septohippocampal area, the nucleus accumbens, and, less frequently, the medullary reticular formation, dorsal motor nucleus of the vagus, and the cortex. The GLP-1R is broadly distributed in the CNS, in contrast to the NTS, where GLP-1 production and distribution are limited [4].…”

“…GLP-1R/gastric inhibitory polypeptide receptor (GIPR) dual agonists inhibited microgliosis, astrogliosis, and the expression of toll-like receptor-4 in a manner comparable to GLP-1 mimetics, however, they had a greater impact. Analogs of the GLP-1R (such as oxyntomodulin and exenatide) promote synaptogenesis, preserve synapses, increase hippocampus synaptic plasticity, and improve learning and memory [4,49].…”

“…Neurofibrillary tangles, which are shaped by hyperphosphorylated tau protein and can build up into oligomers and/or Aβ plaques, are one of the neuro-pathological characteristics of AD. Aβ buildup in AD has the potential to damage synapses and cause neuroinflammation by triggering astroglia and microglia cells [4,52,53].…”

“…Due to a lack of clinical efficacy or unpleasant side effects, several neuroprotective therapies intended to reduce neuronal death have been ineffective. This prompted researchers to investigate alternative therapeutic applications, such as peptides as neuroprotective agents [1][2][3][4][5]. Notably, several peptides have been applied in clinical settings, including erythropoietin (EPO), glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), and oxytocin (OXT) [6][7][8][9][10][11][12].…”