GLP-1 and the Degenerating Brain: Exploring Mechanistic Insights and Therapeutic Potential

Abstract

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades-cAMP/PKA, PI3K/Akt, and MAPK pathways-that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood-brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications.

Keywords: Alzheimer’s disease; GLP-1 receptor agonists (GLP-1RAs); Parkinson’s disease; clinical trials; neurodegeneration; neuroinflammation; stroke; synaptic plasticity.

Figure 1

Regulation of Feeding and Energy via Gut–Brain GLP-1 Pathways. The figure above illustrates GLP-1 secretion from enteroendocrine L cells and its actions through humoral and neural pathways. GLP-1 released in the gut may either activate vagal nerves in the intestinal epithelial cells or travel through the humoral route, crossing the blood–brain barrier to interact with neurons in the brain. In the brain, GLP-1 engages with arcuate nucleus neurons (ARC) in the hypothalamus or neurons of the nucleus tractus solitarius (NTS) in the brainstem to regulate feeding and energy.

Figure 2

Diagrams of coronal sections showing the distribution of GLP-1R-expressing cell bodies in the mouse brain. Green circles represent the presence of GLP-1R immunoreactive somata (neuronal cell body). The density of the green circles indicates the relative density of the GLP-R-positive somata in each brain region. Brain-section diagrams are based on the Paxinos Mouse Brain Atlas and numerical values next to each section indicate the rostro-caudal position in relation to Bregma. SCol, superior colliculus; PAG, periaqueductal grey area; MG, medial geniculate nucleus; PAG, periaqueductal grey area; VTA, ventral tegmental area; PVT, thalamic paraventricular nucleus; VPM, ventral posteromedial thalamic nucleus; Pir, piriform cortex; CeA, central amygdala; BLA, basolateral amygdala; MeA, medial amygdala; DMH, dorsomedial hypothalamus; VMH, ventromedial hypothalamus; ARC, arcuate nucleus; SFO, subfornical organ; Rt, reticular nucleus; LH, lateral hypothalamus; 3V, Third Ventricle. The illustration’s concept was primarily derived from the data presented in the article [16].

Figure 3

The GLP-1R mRNA expression in different regions of human brain. The red and yellow circles indicate the localization of GLP-1R mRNA based on the data presented in the article [18] and The Human Protein Atlas (HPA), respectively. While the density of the red circles indicates the level of expression of the GLP-1R mRNA in the specific brain region; the number of the yellow circles indicates the approximate transcripts per million (nTPM) mentioned in the HPA. Illustration was created using Biorender.com.

Figure 4

Mechanism of GLP-1 Mediated Neuroprotection. The interactions between GLP-1 and its receptor GLP-1R in presynaptic neurons are depicted in the smaller image on the left. The black rectangle inset is magnified on the right to illustrate the intracellular signaling cascades that result in neuroprotection. GDP—Guanosine diphosphate; GTP—Guanosine triphosphate; cAMP—Cyclic adenosine monophosphate; PIP2—Phosphatidylinositol 4,5-bisphosphate; PIP3—Phosphatidylinositol (3,4,5)-trisphosphate; IRS—Insulin Receptor Substrate; MPZ—Myelin protein zero; PMP22—Peripheral myelin protein 22.