Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease

Abstract

Activation of microglia by classical inflammatory mediators can convert astrocytes to 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 (GLP-1R) agonists have been touted as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)3-13. The mechanisms by which GLP-1R agonists are neuroprotective are not known. Here we show that a potent, brain penetrant long acting GLP-1R agonist NLY01 protects against the loss of dopamine neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) model of sporadic PD14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic (Tg) model of α-synucleinopathy induced neurodegeneration16. We found that NLY01 is a potent GLP-1R agonist with favorable properties that is neuroprotective via the direct prevention of microglial mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of NLY01 favorable properties it should be evaluated in the treatment of PD and related neurologic disorders characterized by microglial activation.

Understanding the Links Between Cardiovascular Disease and Parkinson's Disease

“…If any of the CV drugs have “off target” (ie, independent of their effects on glucose, blood pressure, cholesterol, etc.) beneficial effects on PD neurodegeneration, then trials must focus on single agents and/or drug classes that may share a common mechanism(s) of “neuroprotection.” The GLP‐1 receptor agonists may be interesting because of their potential neuroprotective/neurorestorative properties in a range of animal models alongside data indicating potential mechanisms through antiinflammatory effects on microglia/astrocytic processes or antiapoptotic effects through the Akt/mechanistic target of rapamycin pathway . Whether these effects are distinct or if there is overlap between the neurodegenerative and microvascular disease processes is of clear interest but not yet known.…”

Neuroinflammation in mouse models of Alzheimer's disease

“…Astrocytic phagocytosis has been suggested to engulf and degrade plaque‐associated synaptic dystrophies in APP/PS‐1 mice and AD brain . Furthermore, neurotoxic A1 astrocytes are induced by activated microglia; to this end, a glucagon‐like peptide‐1 receptor agonist was postulated to act as a potential neuroprotective agent through the suppression of A1 astrocytes in a mouse model of Parkinson's disease . Although further classification of astrocyte cell types is required, plaque‐associated reactive astrocytes could protect neurons surrounding amyloid plaques in the early stages of AD pathogenesis.…”

Neuroinflammation in the central nervous system: Symphony of glial cells

“…The M1/M2 and A1/A2 paradigms previously described have been used in a body of work, despite the limitation of the paradigms in the precise reflection of the characteristics of glial cell heterogeneity. These simplified models reaffirm the “two‐sided” character of inflammation, including both pro‐ and anti‐inflammation, and are helpful to explain the pathology of neuroinflammation (Yun et al, ). Therefore, it is necessary to link the current data with previous findings in experimental models and clinical observations, which will help us to more accurately and effectively intervene with the neuroinflammation by regulating the activities of glial cells.…”