In Alzheimer's, excess tau protein damages brain's GPS

January 19, 2017, Columbia University Medical Center
A grid cell from the entorhinal cortex (EC) of the mouse brain, firing repeatedly and uniformly in a grid-like pattern. When a mouse moves through its environment, grid cells are activated, with each cell representing a specific location. This creates a triangular coordinate system that allows for spatial navigation. Several grid cells create a triangular coordinate system that allows for spatial navigation. The accumulation of tau protein in the brain of a mouse model of Alzheimer's disease was shown to disrupt the function of grid cells, causing problems with navigation. The findings explains why Alzheimer's patients tend to wander and get lost. Credit: Lab of Karen Duff, PhD, Columbia University Medical Center

Columbia University Medical Center (CUMC) researchers have 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 in the brain. The findings, in mice, could lead to early diagnostic tests for Alzheimer's and highlight novel targets for treating this common and troubling symptom.

The study was published online today in the journal Neuron.

An estimated 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 (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC.

Dr. Duff and her colleagues focused their investigations on excitatory , 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 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.

"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," said Eric Kandel, MD, Nobel laureate, University Professor and Kavli Professor of Brain Science at CUMC. "This is a classic advance in our understanding of the early stages of Alzheimer's disease."

"This study is the first to show a link between grid cells and Alzheimer's disease," said Edvard E. Moser, Nobel laureate and head of the Kavli Institute for Systems Neuroscience at Norwegian University of Science and Technology. "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."

The findings raise the possibility that could be treated by correcting this imbalance through transcranial stimulation, deep-brain stimulation, or light-based therapy.

"We have a lot to learn about grid cells and how they are affected by Alzheimer's disease," said Gustavo A. Rodriguez, PhD, a postdoctoral research scientist in the Taub Institute and a co-author of the paper. "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," said Dr. Duff, "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."

The study is titled, "Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease."

Explore further: Toxic Alzheimer's protein spreads through brain via extracellular space

Related Stories

Toxic Alzheimer's protein spreads through brain via extracellular space

July 18, 2016
A toxic Alzheimer's protein can spread through the brain—jumping from one neuron to another—via the extracellular space that surrounds the brain's neurons, suggests new research from Columbia University Medical Center.

Grid cells' role in human imagination revealed

March 10, 2016
Evidence of grid cell activity has been seen in healthy volunteers asked to imagine moving through an environment in new UCL (University College London) research funded by the Medical Research Council and Wellcome Trust.

Study shows Alzheimer's disease may spread by 'jumping' from one brain region to another

February 1, 2012
For decades, researchers have debated whether Alzheimer's disease starts independently in vulnerable brain regions at different times, or if it begins in one region and then spreads to neuroanatomically connected areas. A ...

Speed data for the brain's navigation system

December 6, 2016
In order to guide us accurately through space, the brain needs a "sense" of the speed of our movement. But how do such stimuli actually reach the brain? Researchers at the German Center for Neurodegenerative Diseases (DZNE) ...

New model for studying Alzheimer's disease

November 21, 2016
The vast majority of Alzheimer's disease cases are not directly inherited but linked to environmental and genetic factors. Yet most models used for studying Alzheimer's in animals mimic the inherited form of the disease.

New insights into causes of loss of orientation in dementia

January 12, 2016
New research has revealed how disease-associated changes in two interlinked networks within the brain may play a key role in the development of the symptoms of dementia.

Recommended for you

Data detectives shift suspicions in Alzheimer's to inside villain

February 20, 2018
The mass pursuit of a conspicuous suspect in Alzheimer's disease may have encumbered research success for decades. Now, a new data analysis that has untangled evidence amassed in years of Alzheimer's studies encourages researchers ...

Not being aware of memory problems predicts onset of Alzheimer's disease

February 15, 2018
Doctors who work with individuals at risk of developing dementia have long suspected that patients who do not realize they experience memory problems are at greater risk of seeing their condition worsen in a short time frame, ...

Researchers successfully reverse Alzheimer's disease in mouse model

February 14, 2018
A team of researchers from the Cleveland Clinic Lerner Research Institute have found that gradually depleting an enzyme called BACE1 completely reverses the formation of amyloid plaques in the brains of mice with Alzheimer's ...

Poor fitness linked to weaker brain fiber, higher dementia risk

February 14, 2018
Scientists have more evidence that exercise improves brain health and could be a lifesaving ingredient that prevents Alzheimer's disease.

Compound prevents neurological damage, shows cognitive benefits in mouse model of Alzheimer's disease

February 7, 2018
The supplement nicotinamide riboside (NR) – a form of vitamin B3 – prevented neurological damage and improved cognitive and physical function in a new mouse model of Alzheimer's disease. The results of the study, conducted ...

Positive attitudes about aging reduce risk of dementia in older adults

February 7, 2018
Research has shown that older persons who have acquired positive beliefs about old age from their surrounding culture are less likely to develop dementia. This protective effect was found for all participants, as well as ...

0 comments

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.