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Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease
Seung Pil Yun1,2,3, Tae-In Kam1,2, Nikhil Panicker1,2
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract:
Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease3-13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson's disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.
Insights
NLY01, a glucagon-like peptide-1 receptor (GLP1R) agonist, prevents the conversion of astrocytes to a toxic A1 phenotype. This neuroprotective action may offer a new treatment for Parkinson's disease and other neurological disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Microglial activation drives astrocyte conversion to a neurotoxic A1 phenotype in neurological diseases.
- Glucagon-like peptide-1 receptor (GLP1R) agonists show potential neuroprotection in Alzheimer's and Parkinson's disease.
- The precise neuroprotective mechanisms of GLP1R agonists remain largely unknown.
Purpose of the Study:
- To investigate the neuroprotective effects of the GLP1R agonist NLY01.
- To elucidate the mechanism by which NLY01 confers neuroprotection.
- To evaluate NLY01 in mouse models of Parkinson's disease and alpha-synucleinopathy.
Main Methods:
- Utilized the alpha-synuclein preformed fibril (α-syn PFF) mouse model for Parkinson's disease.
- Employed the human A53T alpha-synuclein (hA53T) transgenic mouse model for alpha-synucleinopathy.
- Assessed neuroprotection by measuring dopaminergic neuron loss, behavioral deficits, and neuropathological abnormalities.
Main Results:
- NLY01 demonstrated neuroprotection against dopaminergic neuron loss and behavioral deficits in Parkinson's disease models.
- NLY01 treatment prolonged survival and reduced neuropathology in the hA53T mouse model.
- NLY01 directly prevents microglial-mediated conversion of astrocytes to the toxic A1 phenotype.
Conclusions:
- NLY01 is a potent, brain-penetrant GLP1R agonist with significant neuroprotective properties.
- NLY01's mechanism involves preventing the astrocyte A1 neurotoxic phenotype.
- NLY01 warrants further investigation for treating Parkinson's disease and related neuroinflammatory disorders.
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