International Journal of Drug Delivery Technology · May 22, 2026
Pleiotropic Neuroprotection of GLP-1 Receptor Agonists:From Synaptic Plasticity to Autophagy-Mediated Proteostasis in Neurodegeneration
By Tripathi D, Sharma N, Nayak RAK et al.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) - initially launched for the treatment of type 2 diabetes mellitus and obesity - are a class of promising neuroprotective drugs with multi-faceted mechanisms of action beyond glucose control. In this comprehensive review, we summarise the rapidly growing preclinical and clinical data showing that GLP-1 RAs have pleiotropic neuroprotective effects such as promoting synaptic plasticity, reducing neuroinflammation, restoring mitochondrial function, inhibiting oxidative stress, enhancing adult neurogenesis, and - most excitingly - regulating autophagy-mediated protein homeostasis (proteostasis) via mTORC1/AMPK/Beclin-1 signalling pathways. We explore the molecular basis of GLP-1 receptor (GLP-1R) agonism in the brain, describe intrinsic signalling cascades via cAMP/PKA/CREB, PI3K/Akt/GSK-3β and NFκB pathways, and draw their connections to the hallmark aggregating proteins - amyloid beta (Aβ) and tau in Alzheimer's disease (AD), alpha-synuclein (α-syn) in Parkinson's disease (PD), TDP-43/FUS in Amyotrophic lateral sclerosis (ALS) and polyglutamine repeats in Huntington's disease (HD). Clinical evidence, such as the EXENATIDE-PD randomised controlled trial, ELAD, LIRAFLOW, SELECT sub-analysis and several CVOT post-hoc cognitive studies, are evaluated. We also discuss the penetration and variable CNS bioavailabilities of different agents, the relationship with brain insulin resistance, and the revolutionary promise of new dual/triple incretin receptor agonists. We flag the remaining questions of dosing, patient selection, biomarker discovery and mechanistic knowledge gaps, and chart a course for future translational research