The spatial disorientation that leads to wandering in many Alzheimer’s disease patients is caused by the accumulation of tau protein in navigational nerve cells in the brain, researchers at Columbia University Medical Center (CUMC) have discovered.
The findings, in mice, could open the door to early diagnostic tests for Alzheimer’s and highlight novel targets for treating this common and troubling symptom.
It is estimated that three out of five people with Alzheimer’s disease wander and get lost, usually beginning in the early stages of the disease, leaving them vulnerable to injury. Researchers suspect that these problems originate in an area of the brain known as the entorhinal cortex (EC).
The EC plays a key role in memory and navigation and is among the first brain structures affected by the buildup of neurofibrillary tangles that are largely composed of tau, a hallmark of Alzheimer’s disease.
“Until now, no one has been able to show how tau pathology might lead to navigational difficulties,"
said co-study leader Karen E. Duff, PhD, professor of pathology & cell biology at CUMC.
Excitatory Grid Cells
Dr. Duff and her colleagues focused their investigations on excitatory grid cells, a type of nerve cell in the EC that fires in response to movement through space, creating a grid-like internal map of a person’s environment. The researchers made electrophysiological recordings of the grid cells of older mice — including mice engineered to express tau in the EC (EC-tau mice) and normal controls — as they navigated different environments.
Spatial cognitive tasks revealed that the EC-tau mice performed significantly worse compared to the controls, suggesting that tau alters grid cell function and contributes to spatial learning and memory deficits, according to co-study leader Abid Hussaini, PhD, assistant professor of neurobiology in Pathology and Cell Biology and the Taub Institute.
Detailed histopathological analysis of the mouse brains revealed that only the excitatory cells, but not the inhibitory cells, were killed or compromised by pathological tau, which probably resulted in the grid cells firing less.
“It appears that tau pathology spared the inhibitory cells, disturbing the balance between excitatory and inhibitory cells and misaligning the animals' grid fields,"
said co-first author Hongjun Fu, PhD, associate research scientist in the Taub Institute, who led the immunohistological and behavior studies.
Potential Spatial Disorientation Treatment
Edvard E. Moser, Nobel laureate and head of the Kavli Institute for Systems Neuroscience at Norwegian University of Science and Technology, said:
“This study is the first to show a link between grid cells and Alzheimer’s disease. These findings will be crucial for future attempts to understand the development of early Alzheimer’s disease symptoms, including the tendency to wander and get lost."
Co-author Gustavo A. Rodriguez, PhD, a postdoctoral research scientist in the Taub Institute, adds:
“We have a lot to learn about grid cells and how they are affected by Alzheimer’s disease. We don’t yet know what percentage of healthy grid cells are needed for proper navigation or whether this system is rescuable once it has been compromised."
Karen E. Duff et al. Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction and Spatial Memory Deficits Reminiscent of Early Alzheimer’s Disease Neuron, January 2017 DOI: 10.1016/j.neuron.2016.12.023
Image: A grid cell from the entorhinal cortex (EC) of the mouse brain, firing repeatedly and uniformly in a grid-like pattern. Credit: Lab of Karen Duff, PhD, Columbia University Medical Center