Tangled path of Alzheimer's-linked brain cells mapped in mice

June 9, 2014
This shows the paths (red) taken by a single cholinergic neuron as it branches through a thin section of the forebrain of a mouse. Credit: eLife

By studying laboratory mice, scientists at The Johns Hopkins University have succeeded in plotting the labyrinthine paths of some of the largest nerve cells in the mammalian brain: cholinergic neurons, the first cells to degenerate in people with Alzheimer's disease.

"For us, this was like scaling Mount Everest," says Jeremy Nathans, Ph.D., professor of molecular biology and genetics, neuroscience, and ophthalmology at the Johns Hopkins University School of Medicine. "This work reveals the amazing challenges that cholinergic neurons face every day. Each of these cells is like a city connected to its suburbs by a single, one-lane road, with all of the emergency services located only in the city. You can imagine how hard it would be in a crisis if all of the emergency vehicles had to get to the suburbs along that one road. We think something like this might be happening when cholinergic neurons trying to repair the damage done by Alzheimer's disease."

Each cholinergic neuron, Nathans explains, has roughly 1,000 branch points. If lined up end to end, one neuron's branches would add up to approximately 15 times the length of the mouse brain. But all of the branches are connected by a single, extremely thin "pipeline" to one hub—the cell body—that provides for the needs of the branches. The challenge of moving material through this single pipeline could make it very difficult for cholinergic neurons to combat the challenges that come with a disorder like Alzheimer's disease, he says. Now, by mapping the branches and pipelines, scientists will likely get a better fix on what happens when the neurons fail to meet the challenges.

A summary of the research was published online in the journal eLife on May 7.

Tangled path of Alzheimer's-linked brain cells mapped in mice
This shows the cholinergic neurons of a healthy mouse at 12 months of age (left) compared to those of a mouse with "Alzheimer's disease" at 7 months (right). The diseased neurons are fragmented and show clumps of what may be cellular debris. Credit: eLife

Cholinergic neurons are among the largest neurons in the mammal brain. Named for their release of a chemical messenger called acetylcholine, they number only in the thousands in mouse brains, a tiny fraction of the 50 to 100 million total neurons. Their cell bodies are located at the base of the brain near its front end, but their branches extend throughout the cerebral cortex, the outermost, wrinkled layer of "grey matter" that is responsible for the mind's most advanced intellectual functions. Therefore, although there are relatively few cholinergic neurons, they affect a very large part of the brain, Nathans says.

Due to the technical challenge of visualizing the complicated paths of hundreds of tiny branches from a single neuron tangled within millions of other neurons, the actual size and shape of individual cholinergic neurons—and the territory they cover—had been unknown until now, Nathans says. Using genetic engineering methods, the Nathans team programmed several cholinergic neurons per mouse to make a protein that could be seen with a colored chemical reaction. Critical to the success of the work was the ability to limit the number of cells making the protein—if all of the cholinergic neurons made the protein, it would have been impossible to distinguish individual branches.

Because microscopes cannot see through thick tissue, Nathans and his team preserved the mouse brains and then thinly sliced them to produce serial images. The branching path of each neuron was then painstakingly reconstructed from the serial images and analyzed. In adult mice, he says, the average length of the branches of a single cholinergic neuron, lined up end to end, is 31 cm (12 inches), varying from 11 to 49 cm (4 to 19 inches). The average length of a mouse brain is only 2 cm—a bit less than one inch. Although each cholinergic neuron, on average, contains approximately 1,000 branch points, they vary significantly in the extent of the territory that they cover.

The researchers used the same techniques to study the cholinergic neurons of mice with a rodent form of Alzheimer's disease and found that the branches were fragmented. They also found clumps of material that may have been debris from the disintegrating branches.

This shows actual and magnified dimensions of a human cholinergic neuron. (Top) Total length of neuron branches if placed end to end; (middle) length of central "pipeline" connecting the branches to the cell hub (soma; bottom). Credit: eLife

Although the cholinergic neurons of human brains have not been individually traced, Nathans' team was able to calculate that the average cholinergic neuron in the human has a total branch length of approximately 100 meters, a bit longer than a football field. "That is a really long pipeline, especially if one considers that the pipes have diameters of only 30 thousandths of a millimeter, far narrower than a human hair," says Nathans.

He adds, "Although our study only defined a few simple, physical properties of these , such as size and shape, it has equipped us to form and test better hypotheses about what goes wrong with them during disease."

Explore further: Researchers crack degeneration process that leads to Alzheimer's

More information: Paper: www.dx.doi.org/10.7554/eLife.02444

Related Stories

Alzheimer's to be diagnosed online

January 8, 2013

(Medical Xpress)—The early onset of Alzheimer's disease could be detected using a simple online test, according to scientists from the Queensland Brain Institute (QBI) at The University of Queensland (UQ).

Neuron tells stem cells to grow new neurons

June 2, 2014

Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility ...

Recommended for you

New insights on how cocaine changes the brain

November 25, 2015

The burst of energy and hyperactivity that comes with a cocaine high is a rather accurate reflection of what's going on in the brain of its users, finds a study published November 25 in Cell Reports. Through experiments conducted ...

Can physical exercise enhance long-term memory?

November 25, 2015

Exercise can enhance the development of new brain cells in the adult brain, a process called adult neurogenesis. These newborn brain cells play an important role in learning and memory. A new study has determined that mice ...

Umbilical cells help eye's neurons connect

November 24, 2015

Cells isolated from human umbilical cord tissue have been shown to produce molecules that help retinal neurons from the eyes of rats grow, connect and survive, according to Duke University researchers working with Janssen ...

Brain connections predict how well you can pay attention

November 24, 2015

During a 1959 television appearance, Jack Kerouac was asked how long it took him to write his novel On The Road. His response – three weeks – amazed the interviewer and ignited an enduring myth that the book was composed ...

No cable spaghetti in the brain

November 24, 2015

Our brain is a mysterious machine. Billions of nerve cells are connected such that they store information as efficiently as books are stored in a well-organized library. To this date, many details remain unclear, for instance ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.