Rare disease yields clues about broader brain pathology

Alexander disease is a devastating brain disease that almost nobody has heard of — unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

(Image: A mutant gene that causes the deadly Alexander disease creates an overgrowth of the protein GFAP in mouse brain cells called astrocytes (right) compared to normal brain cells (left))

Regardless of the age when it begins, Alexander disease is always fatal. It typically results from mutations in a gene known as GFAP (glial fibrillary acidic protein), leading to the formation of fibrous clumps of protein inside brain cells called astrocytes.

Classically, astrocytes and other glial cells were considered “helpers” that nourish and protect the neurons that do the actual communication. But in recent years, it’s become clear that glial cells are much more than passive bystanders, and may be active culprits in many neurological diseases.

Now, in a report in the Journal of Neuroscience, researchers at UW-Madison show that Alexander disease also affects neurons, and in a way that impacts several measures of learning and memory.

Mice were engineered to contain the same mutation in GFAP that is found in human patients. Their astrocytes spontaneously increased production of GFAP, the same response found after many types of injury or disease in the brain. In Alexander disease, the result is an increase in mutant GFAP that is “toxic to the cell, and unfortunately astrocytes respond by making more GFAP,” says first author Tracy Hagemann, an associate scientist with the university’s Waisman Center.

While GFAP is usually found in astrocytes, it also occurs in neural stem cells, a population of cells that persist in some areas of the brain to continually spawn new neurons throughout adulthood. In the mouse versions of Alexander disease, neural stem cells are present, but they fail to develop into neurons, Hagemann says. “Think of a garden where your green beans never sprouted. Was it too cold for them to sprout, or was there another problem? Something similar is happening with these neural stem cells. They are present, but inert, and we’re not sure why.”

The shortage of new neurons could explain why the mice with excess GFAP failed a test that required them to remember the location of a submerged platform in a tub of water.

The report is “the first to suggest that the problems in Alexander disease extend beyond just the white matter and astrocytes, and may provide a clue to the problems with learning and memory that are such prominent features in the human disease,” says lab leader Albee Messing, a professor of comparative biosciences in the UW School of Veterinary Medicine.

One immediate question that the team will try to answer is whether the same defect in stem cells can be found in autopsy samples stored over many years to allow just this kind of investigation.

Still to be clarified is whether the mutation affects the neural stem cells directly, or whether it acts through other astrocytes that are nearby. “We do know that the astrocytes become activated with this GFAP mutation,” Hagemann says. “That activation — a kind of inflammation — could be making the environment hostile to young neurons. Or the mutation could be changing the neural stem cells themselves in some other way.

"Medicine advances by teasing things apart,” says Hagemann. “A single mutation can work in different ways — through different chains of cause and effect leading to different symptoms of a disease. In this case it’s like the old question of nature versus nurture. Was the stem cell born bad — was it genetically doomed? Or were the reactive astrocytes in the neighborhood a toxic influence? Or both? This is an important question for Alexander disease and other brain deteriorating disorders, especially with the current focus on stem cells as a source for new neurons and therapy.”

Already, the Waisman group is screening drugs that might slow GFAP production. Eventually, Hagemann says, the work may illuminate the role of astrocyte dysfunction in other neural diseases featuring aggregates of misformed proteins, including ALS, Parkinson’s, and Alzheimer’s disease.

List: Astrocyte Functions

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Astrocytes are a special kind of stellate-shaped brain cells that are found throughout the central nervous system and that play a supportive role for neurons. For a long time, astrocytes were thought of as merely providing “assistance” for neuron function and survival. However, the discovery that astrocytes express voltage-gated channels and neurotransmitter receptors suggests the possibility of an active role for astrocytes in neuronal communication. Astrocytes primarily originate come from either radial glia cells or from cells in the sub ventricular zone and can be visualized with glial fibrillary acidic protein (GFAP). Below is an image of GFAP staining for astrocytes. 

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Other groups of glia: 

  • Oligodendrocytes: Provide myelin sheath in neurons present in the central nervous system (CNS). Each oligodendrocyte can myelinate multiple axons. 
  • Schwann Cells: Myelinate axons of neurons present in the peripheral nervous system (PNS). Schwan cells, however, only myelinate one axon. 
  • Microglia: Derived from bone marrow and function as antigen presenting cells. Microglia have phagocytic activity, which means they “eat up” (or clear) cellular debris and their roles are predominantly host defense. 

Astrocyte Functions:

  • Regulation of brain extracellular pH via secretion of acid into the extracellular space (aka potassium buffering). Other regulatory functions of astrocytes include limiting the rise of both extracellular potassium (K+) and pH during neural activity. In addition, astrocytes can take up potassium in a variety of ways: Na+-K+ exchange, K+-Cl- cotransport and other K+ channels characterized by distinct properties. 
  • Regulating the uptake of glutamate near the synaptic cleft. 
  • Astrocytes can serve as signaling elements within an astrocyte network, between astrocytes and blood vessels, and/or between astrocytes and neurons. For example, astrocytes can signal to other neurons via Ca+2 oscillations (otherwise known as calcium waves). These calcium waves can come about in two ways: they are either triggered by neural activity (such as activation of astrocyte glutamate receptors) or spontaneoulsy via calcium release from internal stores and activation of IP3 receptors. Astrocytes may also serve as neurotransmitter transporters and receptors as well as aiding in neurotransmitter catabolism.
  • Modulate synaptic and neural activity via “gliotransmission”. Known gliotransmitters (chemicals that can act on neighboring neurons, glial cells or vessels) include glutamate, cytokines, ATP, and D-serine.  As illustrated below, astrocyte processes govern the amount of neurotransmitter spillage around synapse, thus controlling lateral spread of excitation. 
  • Modulation of brain vascular tone (i.e. vasodilation/vasoconstriction) and promotion of neurovascular coupling. Basically, astrocytes regulate cerebral blood flow. Moreover, vascular tone depends on the release of vascular agents into the perivascular space. 
  • Control of synapse formation, stabilization and function as well as neurogenesis. These roles have been predominantly explored in the context of brain pathology and psychiatric disorders like ALS, Alzheimer’s, brain tumors, traumatic brain injury and ischemia. 


Chesler, Mitch. Properties of the brain, extracellular space and astrocyte function. Lecture given as part of the cellular neuroscience course. Fall 2009. 

Volterra A & Meldolesi J. 2005. Astrocytes, from brain glue to communication elements. Nature Reviews Neuroscience. 6 (8): 626-40. 

Image of the Week - July 4, 2016

CIL:40197 -

Description: Mosaic image of mouse cerebellum reconstructed through automated acquisition and stitching of over 1700 individual tiles in the X, Y and Z planes, triple labeled for astrocytes (GFAP; Red), gap junctions (Connexin 43; Green) and nuclei (DAPI; Blue), and imaged using multiphoton microscopy. The contrast and brightness were adjusted on the thumbnail image for display purposes. This image has been downsampled from the raw data image which can be accessed using the link provided to the Cell Centered Database.

Authors: Angela Cone, Gina Sosinsky, and Maryann Martone

Licensing: Attribution Only: This image is licensed under a Creative Commons Attribution License