“Transportation” May Be at the Heart of Alzheimer’s Disease

Scientists at The Johns Hopkins University have mapped the intricate, far-reaching branches of cholinergic neurons in the mouse brain—cells that are among the first to deteriorate in Alzheimer’s disease. By tracing these neurons in laboratory mice, the research team has revealed how the physical layout and internal “transportation” demands of these cells may contribute to their vulnerability in neurodegenerative conditions.

“For us, this was like scaling Mount Everest,” says Jeremy Nathans, Ph.D., a professor of molecular biology and genetics, neuroscience, and ophthalmology at the Johns Hopkins University School of Medicine. Nathans likens each cholinergic neuron to a city connected to a vast suburban area by a single narrow road, with essential services concentrated at the city hub. When damage occurs, all supplies and repair materials must travel along that one narrow connection, creating a severe logistical challenge. The team proposes that this constrained internal transport might help explain why cholinergic neurons struggle to repair damage associated with Alzheimer’s disease.

Cholinergic neurons are among the largest neurons in mammal brains and are named for releasing the neurotransmitter acetylcholine. In the mouse brain they number only in the thousands, a tiny fraction of the tens of millions of total neurons, yet their branches extend widely across the cerebral cortex—the outer layer of the brain responsible for higher cognitive functions. Because each cholinergic neuron reaches across a large cortical territory, even a small population of these cells has outsized influence over brain activity.

Until now, the full size, shape, and territories of individual cholinergic neurons were unclear because their many fine branches are deeply interwoven with millions of other nerve cells. Nathans and colleagues overcame this technical barrier by using genetic engineering to label a very limited number of cholinergic neurons in each mouse with a visible protein. Limiting the number of labeled cells was critical: if many cholinergic neurons had been marked at once, their branches would have overlapped and individual cells could not be resolved.

The team preserved mouse brains, sliced them into very thin serial sections, and imaged these sections with microscopy. They then reconstructed the full branching patterns of single neurons from the serial images. In adult mice, the researchers found that the total length of branches from one cholinergic neuron, if aligned end to end, averaged about 31 centimeters (approximately 12 inches), with a range from 11 to 49 centimeters (4 to 19 inches). For context, the average mouse brain measures about 2 centimeters—less than an inch. Each cholinergic neuron typically contains roughly 1,000 branch points, though the size and extent of their territories vary substantially between cells.

When the same mapping techniques were applied to a mouse model of Alzheimer’s disease, the cholinergic axons displayed fragmentation and contained clumps of material that likely represent debris from degenerated branches. These structural disruptions support the idea that impaired transport along the narrow connections from the cell body to distant branches may contribute to degeneration in disease.

Although individual cholinergic neurons in the human brain have not been traced directly in this study, the team estimated that an average human cholinergic neuron would extend roughly 100 meters in total branch length—longer than a football field. Nathans points out that this tremendous span relies on internal pipelines whose diameters measure only about 0.03 millimeters, far thinner than a human hair. Such extreme geometry places demanding logistical requirements on intracellular transport systems that ferry proteins, organelles, and repair materials from the cell body out to distant terminals.

“Our study defines basic physical properties of these neurons—size, branching pattern, and territory—and gives us new, testable hypotheses about what fails in disease,” Nathans says. By clarifying the structural constraints that cholinergic neurons face, the work sets the stage for experiments that can examine how transport breakdown, branch fragmentation, and debris accumulation contribute to cognitive decline in Alzheimer’s disease.

Other authors on the report include Hao Wu and John Williams, both of the Johns Hopkins University School of Medicine. The published summary appeared in the journal eLife on May 7.

This research was supported by grants from the Human Frontier Science Program, the Howard Hughes Medical Institute, and the Brain Science Institute of The Johns Hopkins University.

Contact: Catherine Kolf — Johns Hopkins Medicine
Source: Johns Hopkins Medicine press release
Image credit: Nathans Lab / eLife
Original research: Abstract for “Complete morphologies of basal forebrain cholinergic neurons in the mouse” by Hao Wu, John Williams, and Jeremy Nathans in eLife. Published online May 7, 2014. DOI: 10.7554/eLife.02444