Prevention of Harmful Astrocyte Activation as a Therapy for Parkinson's Disease

Researchers have recently investigated means to interfere in on a one of the later consequences in neurodegenerative conditions, in which the supporting astrocyte cells in the brain become actively harmful to the neurons that they normally aid and protect. Astrocytes are triggered into this state at least in part by the inflammatory dysregulation of microglia, a class of innate immune cells of the central nervous system. Aging brings rising levels of chronic inflammation throughout the body, a consequence of processes such as the accumulation of senescent cells and malfunctioning of the immune system. The evidence clearly shows that this inflammation contributes to the progression of all of the common age-related conditions, and neurodegenerative diseases are no exception.

The focus in the research materials noted here is on Parkinson's disease, but the mechanism is more broadly applicable. All older individuals suffer to some degree from inflammation of the central nervous system, and the more of it there is, the worse off they are. Sabotaging one of the numerous consequences of this inflammatory state is better than nothing, but it isn't as good as finding ways to address the roots of the issue. In this case, that would be the causes of what has come to be known as inflammaging, the decline of the immune system into simultaneous incompetence and excess activity.

There are a number of strategies that could be pursued effectively today, even given the present poor state of knowledge of the precise cellular and biochemical details of later stage aging. Regeneration of the thymus and replacement of hematopoietic stem cells to restore a youthful supply of immune cells; clearance of the existing immune system to remove malfunctioning and maladapted cells; clearance of senescent cells to remove their inflammatory signals; and so forth. While some companies are working in these areas, all in all too little effort is being directed towards these and related strategies that are in principle capable of turning back immune aging.

Experimental Drug Stops Parkinson's Disease Progression in Mice

NLY01 works by binding to glucagon-like peptide-1 receptors on the surface of certain cells. Similar drugs are used widely in the treatment of type 2 diabetes to increase insulin levels in the blood. Though past studies in animals suggested the neuroprotective potential of this class of drugs, researchers had not shown directly how it operated in the brain. To find out, they tested NLY01 on three major cell types in the human brain: astrocytes, microglia, and neurons. They found that microglia, a brain cell type that sends signals throughout the central nervous system in response to infection or injury, had the most sites for NLY01 to bind to - two times higher than the other cell types, and 10 times higher in humans with Parkinson's disease compared to humans without the disease.

Microglia secrete chemical signals that convert astrocytes - the star shaped cells that help neurons communicate with their neighbors - into aggressive "activated" astrocytes, which eat away at the connections between cells in the brain, causing neurons to die off. Researchers speculated that NLY01 might stop this conversion. In a preliminary experiment in laboratory-grown human brain cells, the researchers treated human microglia with NLY01 and found that they were able to turn the activating signals off. When healthy astrocytes were combined with the treated microglia, they did not convert into destructive activated astrocytes and remained healthy neuroprotective cells.

Researchers tested the drug's effectiveness in mice engineered to have a rodent version of Parkinson's disease. They injected the mice with alpha-synuclein, the protein known to be the primary driver of Parkinson's disease, and treated the mice with NLY01. Similar but untreated mice injected with alpha-synuclein showed pronounced motor impairment over the course of six months in behavioral tests. However, the researchers found that the mice treated with NLY01 maintained normal physical function and had no loss of dopamine neurons, indicating that the drug protected against the development of Parkinson's disease.

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

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases. 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 disease.

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 disease. 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 neurodegeneration.

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. NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.


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