Journal Club

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Journal Club: Microglial protein trafficking could play a role in neurodegenerative disorders

Without VPS35, microglia, shown here in an SEM, fail to break down proteins in mice, leading neighboring tissues to show signs of neurodegeneration. Credit: Image courtesy of ScienceSource/John Zajicek

Without the protein VPS35, microglia–shown here in a scanning electron micrograph–fail to break down proteins in mice, leading neighboring tissues to show signs of neurodegeneration. Credit: ScienceSource/John Zajicek

Neurodegenerative conditions such as Alzheimer’s disease (AD) or Parkinson’s are associated with a build-up of insoluble, toxic forms of proteins such as amyloid or tau in the brain. Normally, intracellular protein complexes known as retromers help with recycling and trafficking proteins to prevent this accumulation. One retromer component, a protein named VPS35, is known to be an important player in this process in neurons.

Now, a new study reports that VPS35—which is widespread in other cells as well—also plays a crucial role in maintaining the health of microglia, a type of non-neuronal cells in the brain. Without VPS35, microglia in mice fail to break down proteins appropriately, and neighboring tissues start to show signs of neurodegeneration similar to that seen in AD. The results were published in the Journal of Neuroscience.

The new study is “very timely,” says neurology researcher Li Gan of the University of California, San Francisco, who was not involved with the work. “For a long time, people have focused on the role of trafficking molecules in neurons and very little has been done in other cell types in the brain—even though trafficking molecules are ubiquitous.”

Previous studies had found that microglia in the brains of AD patients are deficient in VPS35, and that this decrease was linked to reduced phagocytosis in vitro and in mice. To further elucidate VPS35’s role, Wen-Cheng Xiong of Case Western Reserve University and her colleagues investigated its functions by creating strains of mice whose microglial cells lacked VPS35.

Compared to control animals, these mice had more densely-packed microglia in the hippocampus, entorhinal cortex, and parts of the dentate gyrus, all brain regions where such changes are linked to an increased vulnerability to AD. This increased density, the researchers report, was a result of increased cell differentiation (to form more microglia), and/or greater migration of microglial cells to these brain regions. Changes in the morphology of these cells indicated that they were also more active.

Mice that lacked VPS35 in their hippocampal microglia also had—in the same brain region—neural stem cells that proliferated more but were less differentiated. The neurons formed in these animals had fewer and less complex dendritic connections. The VPS35-deficient mice also tended to show reduced pleasure-seeking and remained immobile during a forced swim test— behaviors indicative of impaired long-term memory and depression. “Most people see these changes because of neuronal components, so we were a bit surprised to see that a microglial mutation could also have this effect,” Xiong says.

In hopes of understanding how a lack of VPS35 in microglia could cause neuronal defects, the researchers cultured microglia and neurons together in vitro to study their interactions. They found that VPS35-deficient microglia took up greater amounts of post-synaptic proteins and could thus contribute more to pruning adult neurons. Coupled with the undifferentiated neural stem cells, this excessive pruning could alter hippocampal circuitry, contributing to neurodegeneration in the hippocampus—one of the hallmarks of Alzheimer’s disease.

The work is a “really nice study” that adds to our understanding of how microglial activity varies in different brain regions—and why those differences are important to brain functions, says neurology researcher Scott Small of Columbia University, who was not involved with the work. “Retromer is clearly linked to Alzheimer’s disease and Parkinson’s, but we don’t really know all the cell types that are responsible—it could be neurons, microglia, or both,” Small notes. “This work strengthens the links between retromer function and Alzheimer’s disease.”

Categories: Biochemistry | Journal Club | Medical Sciences | Neuroscience and tagged | | | | | | |
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