Cited by 298Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDiabetes Treatment and Management

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

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Kopp, Katherine O., Glotfelty, Elliot J., Li, Yazhou, Greig, Nigel H.·2022·Pharmacological Research

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.

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  • GLP-1R agonists have demonstrated promising neuroprotective effects in neurodegenerative diseases owing to their ability to suppress neuroinflammation.

    “GLP-1R agonists, approved for the treatment of type 2 diabetes and obesity, have demonstrated promising neuroprotective effects in neurodegenerative diseases owing to their ability to suppress neuroinflammation.”
  • Substantial preclinical evidence supports the neuroprotective effects of GLP-1R agonists on cognition in AD, attributed to reducing Aβ pathology, tau phosphorylation, glial activation, and neuroinflammation.

    “Substantial preclinical evidence supports the neuroprotective effects of GLP-1R agonists on cognition in AD, which is attributed to the ability to reduce Aβ pathology, tau phosphorylation, glial activation, and neuroinflammation.”
  • GLP-1 receptor agonists enhance motor performance and dopamine signalling and inhibit the aggregation of α-synuclein in Parkinson's disease models, possibly by regulating the Akt pathway.

    “However, GLP-1 RAs enhance motor performance and dopamine signalling and inhibit the aggregation of α-syn in PD models, possibly by regulating the Akt pathway.423,427”

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  1. [272]Brauer R, Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N, Auld G, Whittlesea C, Wong I, Foltynie T. Diabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes. Brain. 2020; 143(10): 3067– 3076. 33011770 PMC7794498
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Authors
Kopp, K. O., Glotfelty, E. J., Li, Y., & Greig, N. H.
Affiliations
National Institutes of Health (US)
Corresponding author
  • Kopp, Katherine O.
  • Greig, Nigel H.
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2022-12
Volume
186
Pages
106550
ISSN
1043-6618 (ISSN-L)
OpenAlex
W4308952350
Cited by
298
References
306
Citations by year
2026: 92 · 2025: 122 · 2024: 63 · 2023: 21
FWCI
5.31
Type
journal article
Language
en
Open access
Locations
  • Pharmacological Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (AG000333)
  • National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
GLP-1 receptor agonists, neuroinflammation, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, type 2 diabetes, insulin resistance, incretin signaling, drug repurposing, neuroprotection, anti-inflammatory activity
MeSH terms
Glucagon-Like Peptide-1 Receptor, Neuroinflammatory Diseases, Glucagon-Like Peptide-1 Receptor Agonists, Alzheimer Disease, Diabetes Mellitus, Type 2, Humans, Parkinson Disease, Neurodegenerative Diseases, Glucagon-Like Peptide 1, Incretins

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