Aberrant Astrocytes as a Cause of Neurodegenerative Disease

Astrocytes are an important class of support cell in the brain, and one of the most common cell types in brain tissue. They carry out a wide range of tasks, most of which are absolutely essential to the functions performed by neurons. A few years ago, researchers suggested that senescent astrocytes may be responsible for a sizable portion of the progression of neurodegenerative conditions, a proposal expanded and further investigated since then, with a great deal more evidence gathered. Astrocyte behavior in the brain appears to change for the worse with age in a number of ways, not all of which may be connected to cellular senescence, and some of which might be preventable in the near term. The publicity materials here outline some of the most recent findings on this topic, in which the researchers propose that transformed astrocytes are producing some form of signal that results in the death of nearby neurons, and show that these astrocytes are present in neurodegenerative conditions where such cell death occurs:

While most of us haven't heard of astrocytes, these cells are four times as plentiful in the human brain as nerve cells. Now, a team has found that astrocytes, which perform many indispensable functions in the brain, can take on a villainous character, destroying nerve cells and likely driving many neurodegenerative diseases. "We've learned astrocytes aren't always the good guys. An aberrant version of them turns up in suspicious abundance in all the wrong places in brain-tissue samples from patients with brain injuries and major neurological disorders from Alzheimer's and Parkinson's to multiple sclerosis. The implications for treating these diseases are profound." Up to now, the pharmaceutical industry has mostly targeted nerve cells, also known as neurons. But a broad range of brain disorders may be treatable by blocking astrocytes' metamorphosis into toxic cells, or by pharmaceutically countering the neuron-killing toxin those harmful cells almost certainly secrete.

Once thought of as mere packing peanuts whose job it was to keep neurons from jiggling when we jog, astrocytes are now understood to provide critical hands-on support and guidance to neurons, enhancing their survival and shaping the shared connections between them that define the brain's labyrinthine circuitry. It's also known that traumatic brain injury, stroke, infection and disease can transform benign "resting astrocytes" into "reactive astrocytes" with altered features and behaviors. But until recently, whether reactive astrocytes were up to good or evil was an open question. In 2012, researchers resolved that ambiguity when they identified two distinct types of reactive astrocytes, which they called A1 and A2. In the presence of LPS, a component found in the cell walls of bacteria, they observed that resting astrocytes somehow wind up getting transformed into A1s, which are primed to produce large volumes of pro-inflammatory substances. A2s, on the other hand, are induced by oxygen deprivation in the brain, which occurs during strokes. A2s produce substances supporting neuron growth, health and survival near the stroke site.

In a series of experiments using laboratory mice, the scientists identified three pro-inflammatory factors whose production was ramped up after LPS exposure: TNF-alpha, IL-1-alpha and C1q. In the brain, all three of these substances are secreted exclusively by microglia. Each, by itself, had a partial A1-inducing effect on resting astrocytes. Combined, they propelled resting astrocytes into a full-fledged A1 state. Next, the researchers confirmed that A1s jettison the nurturing qualities they'd had as resting astrocytes. Further experiments showed that A1s lose resting astrocytes' capacity to prune synapses that are no longer needed or no longer functional and whose continued existence undermines efficient brain function. Indeed, when the researchers cultured healthy neurons with increasingly stronger concentrations of the broth in which A1s had been bathing, almost all the neurons eventually died. This and other experiments showed that A1s secrete a powerful, neuron-killing toxin.

Finally, the researchers analyzed samples of human brain tissue from patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. In every case, they observed large numbers of A1s preferentially clustering where the disease was most active. For example, in the samples from Alzheimer's patients, nearly 60 percent of the astrocytes present in the prefrontal cortex, a region where the disease takes a great toll, were of the A1 variety. Because A1s are highly toxic to both neurons and oligodendrocytes, these findings strongly imply that A1 formation is helping to drive neurodegeneration in these diseases. An effort to identify the neurotoxin secreted by A1 astrocytes is underway. "We're very excited by the discovery of neurotoxic reactive astrocytes, because our findings imply that acute injuries of the retina, brain and spinal cord and neurodegenerative diseases may all be much more highly treatable than has been thought."

Link: http://med.stanford.edu/news/all-news/2017/01/toxic-brain-cells-may-drive-many-neurodegenerative-disorders.html

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