Arguing a Primary Role for Astrocytes in Neurodegeneration

In the open access paper I'll point out today, the authors provide a high level overview of the evidence that suggests immune cells called astrocytes play a primary role in the progression of age-related neurodegenerative conditions. The immune system of the brain is quite different, somewhat more intricate, and more specialized than its equivalents elsewhere in the body, and those systems are themselves very complex and only partially mapped. The brain is shielded from the sort of haphazard exposure to toxins and pathogens that other tissues must face by the existence of the blood-brain barrier, a shield lining the blood vessels that pass through the brain. The portfolio of tasks carried out by the immune system within that barrier has shifted accordingly. In the brain specialized types of immune cell, neuroglia such as microglia and the aforementioned astrocytes, undertake a very broad range of activities beyond simply sweeping up waste and destroying pathogens, and are tightly integrated into the core functions of the brain. They participate in some of the most important and fundamental neural processes, such as the formation and alteration of connections between neurons, for example.

Most of the common diseases of aging have an inflammatory component. Pathology and degeneration is accelerated by the decline of the immune system into a state of ineffective, constant inflammation. The causes of that decline are discussed elsewhere, and include a sort of misconfiguration perhaps brought on by exposure to persistent pathogens such as cytomegalovirus, and the slow and falling rate of generation of replacement immune cells in adults. Effectively addressing these causes seems a very plausible task for the next couple of decades, based on promising studies in animals from the past few years. In the brain, things are going to be much the same at the high level, but different in the details. A lot of research from recent years points to microglia as the agents of neural inflammation, but the authors here suggest that there is just as much evidence for astrocytes to be involved in the generation of a harmful inflammatory state:

Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System

Since the beginning of the 20th century relentlessly progressive neurological diseases have classically been attributed to a primary neuronal dysfunction. This affirmation applies to Parkinson disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among others. Therefore, most investigations have been carried out under this belief, leading to the coining of the term "neurodegeneration." In the 90s, a new era began that considered the possibility of a more important role of the so far neglected neuroglia. This led to different findings opposed to the belief of the astrocytes sole function being neuronal structural support.

Astrocytes have been found to have a much more active role that the one predicted by the earlier guessers. Particularly, they are involved in the ions exchange with neurons, they are organized as a syncytium that allows them to interchange information with other astrocytes residing in a defined net through different types of Ca+++ signals while regulating the release of signaling molecules involved in the production of trophic factors, transmitters and transporters that when released to the extracellular medium will modulate the synaptic activity synchronizing the neuronal functions. Also they are involved in the extracellular K+ uptake, in synaptogenesis and gene expression; adapting, at the same time, the permeability of the blood-brain barrier to the neuronal and synaptic needs.

Slowly but relentlessly, the results of several studies have confirmed the existence of an active role played not only by the astrocytes but also by microglia. Mounting evidence suggests that astrocytes modulate microglial response, through the establishment of a complex cross-talk between both types of cells mediated by the production of different chemokines and cytokines. Therefore, we think that the broader term primary degenerative disorders of the central nervous system (PDD CNS) alludes to the complex pathology of these diseases (in contrast to the classic term neurodegeneration). An early astrocytic dysfunction in the PDDs of the CNS has been broadly observed. We advocate that these observations obtained from different degenerative pathologies, but mostly from experimental animal studies, may be the trees from a forest characterized by primary astrocytic dysfunction as the main process starting them.

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