The metabolite GLP-1 (9–36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration

Glucagon-like peptide-1 (GLP-1) is widely recognized for its role in glucose regulation. Following secretion, it is rapidly cleaved by the enzyme dipeptidyl peptidase-4 (DPP-IV) into the metabolite GLP-1 (9–36). Historically, this metabolite was considered biologically inactive due to its low affinity for the GLP-1 receptor (GLP-1R). However, given the growing interest in using GLP-1 analogues to treat neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, this study investigates whether GLP-1 (9–36) possesses neuroprotective and anti-inflammatory properties in the central nervous system.

The researchers utilized a variety of cellular models, including human SH-SY5Y neuroblastoma cells (and a variant overexpressing the GLP-1R), human HMC3 and mouse IMG microglial cells, and primary rat neuronal cultures. They challenged these cells with neurotoxic agents such as glutamate, hydrogen peroxide, lipopolysaccharide (LPS), α-synuclein, and amyloid-β. The study assessed cell viability, reactive oxygen species (ROS) production, and inflammatory cytokine release (IL-6 and TNF-α) while using pharmacological inhibitors to identify the signaling pathways involved.

The study demonstrates that GLP-1 (9–36) is not inert. It effectively promotes cell survival and reduces oxidative stress in neuronal cells, particularly in those with higher GLP-1R expression. The metabolite also significantly reduced the release of pro-inflammatory cytokines from microglial cells challenged with LPS. Furthermore, in primary cultures exposed to toxic proteins associated with neurodegeneration (α-synuclein and amyloid-β), GLP-1 (9–36) preserved neurite networks and improved neuronal survival. These effects were mediated through the GLP-1R and involved the activation of PKA and AMPK signaling pathways.