Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment

Abstract

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.

Keywords: Alzheimer’s disease; Glucagon-like peptide-1 (GLP-1); Glucose-dependent insulinotropic peptide (GIP); Incretin mimetic; Insulin resistance; Neurodegeneration; Neuroinflammation; Parkinson’s disease.

Figure 1.

(A) The endogenous secretins have similar amino acid sequences and structures, most notably their favorable cleavage sites for DPP-IV. This results in very short half-lives for these peptides. (B) Exendin-4 is a GLP-1 analog naturally occurring in Gila monster lizard venom. The unique glycine residue at the DPP-IV cleavage site renders the protein unrecognizable by DPP-IV and prolongs the half-life of the peptide. Thus, the exendin-4 backbone has been utilized in the creation of longer-acting synthetic GLP-1R agonists. Figure adapted from Glotfelty et al. 2020 (5).

Figure 2.

Cycle of neuroinflammation. Various cellular stressors (A) can activate microglia (B), which release cytokines, chemokines, and other pro-inflammatory molecules onto neurons (D) and astrocytes (E). These pro-inflammatory molecules can also bind to microglia in an autocrine fashion, triggering activation of additional microglia and further inflammatory signaling (C). Intracellular neuroinflammatory pathways in astrocytes and neurons are stimulated in response. As a result, a subpopulation of astrocytes undergoes reactive astrogliosis and convert to their neurotoxic reactive form (F) and release APOE and APOJ particles containing harmful saturated lipids onto neurons (G), producing further neuroinflammation and neurodegeneration (H). Damaged neurons release DAMPs, cell debris, ATP, and ROS and activate additional microglia (I), recommencing and amplifying the cycle of neuroinflammation.

Figure 3.

Interactions between IR, neuroinflammation, and neurodegenerative disease. Elevated blood sugar levels and dyslipidemia in the blood are consequences of IR (A) that can damage and increase permeability of the BBB (B). BBB damage results in the infiltration of the brain with free fatty acids and excessive glucose (C), thus activating microglia into a pro-inflammatory state (D). These activated microglia release cytokines (E) that stimulate neuroinflammation (F) and reactive astrogliosis (G). Chronic neuroinflammation fuels the development of brain IR, neurodegeneration, and the progression of AD (H).

Figure 4.

Anti-inflammatory mechanisms of GLP-1R/GIPR/GcgR signaling, and sites of receptor expression as evidenced in rats (red superscript), mice (blue superscript), and humans (black superscript). Signaling pathways downstream of secretin receptor activation minimize neuroinflammation, oxidative stress, and apoptosis and provide cytoprotective effects. Sources: (a.) ref(208); (b.) ref(77); (c.) ref(209); (d.) ref(210); (e.) ref(78); (f.) ref(81); (g.) ref(211); (h.) ref(212); (i.) ref(213); (j.) ref(214); (k.) ref(215); (l.) ref(216); (m.) ref(217). Figure adapted from Glotfelty et al. 2019 (12).