Its estimated that three out of five people with Alzheimer's disease (AD) wander and get lost, usually beginning in the early stages of the disease, leaving them vulnerable to injury. Researchers have suspected that along with memory deficiencies the disease also affects the navigational centers—or GPS—of the brain. Now, investigators from Columbia University Medical Center (CUMC) have recently discovered that 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 within the brain.
These new findings in mice, which were just published online in Neuron in an article entitled “Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction and Spatial Memory Deficits Reminiscent of Early Alzheimer’s Disease,” could lead to early diagnostic tests for Alzheimer's and highlight novel targets for treating this common and troubling symptom.
The CUMC team hypothesized that AD patients' 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,” remarked senior study investigator Karen Duff, Ph.D., professor of pathology and cell biology at CUMC and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain.
Dr. Duff and her colleagues centered their research on excitatory grid cells—a type of nerve cell in the EC that fires in response to movement through space—which creates an 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.
Interestingly, intensive 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,” explained co-lead study investigator Hongjun Fu, Ph.D., associate research scientist in the Taub Institute.
“This study clearly shows that tau pathology, beginning in the entorhinal cortex, can lead to deficits in grid cell firing and underlies the deterioration of spatial cognition that we see in human Alzheimer's disease,” noted Nobel Laureate Eric Kandel, M.D., professor of brain science at CUMC, who was not directly involved in the study. “This is a classic advance in our understanding of the early stages of Alzheimer's disease.”
The results of this new study raise the possibility that spatial disorientation could be treated by correcting this imbalance through transcranial stimulation, deep brain stimulation, or even light-based therapy.
“We have a lot to learn about grid cells and how they are affected by Alzheimer's disease,” said co-lead study investigator Gustavo Rodriguez, Ph.D., a postdoctoral research scientist at the Taub Institute. “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.”
In the meantime,” Dr. Duff added, “our findings suggest that it may be possible to develop navigation-based cognitive tests for diagnosing Alzheimer's disease in its initial stages. And if we can diagnose the disease early, we can start to give therapeutics earlier, when they may have a greater impact.”