Antidiabetic GLP-1 Receptor Agonists Have Neuroprotective Properties in Experimental Animal Models of Alzheimer's Disease

Abstract

In addition to the classically accepted pathophysiological features of Alzheimer's disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine-protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD.

Keywords: animal model; glucagon-like peptide-1 receptor agonist; insulin resistance; neurodegeneration; oxidative stress.

Figure 1

General intracellular signaling pathways of the GLP-1R. The G_S protein-coupled GLP-1 receptor, when activated by its endogen ligand, initiates three downstream signaling pathways: cAMP/PKA, PI3K/Akt, and β-arrestin-dependent ERK1/2. cAMP via PKA and Epac triggers Ca²⁺ influx and Ca²⁺ release from the endoplasmic reticulum. ERK/MAPK activation represents a crossroad in GLP-1R signaling, mediating cell-type-dependent biological functions. In pancreatic β-cells, insulin expression, proliferation, and apoptosis inhibition are transmitted by the CREB and β-catenin-TCF/LEF transcription complexes. The AMPK/mTOR balance is crucial for the energetic homeostasis of the cell, regulating protein synthesis and autophagy. Created with BioRender.com.