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 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.
Researchers 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.
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.
The findings raise the possibility that spatial disorientation could be treated by correcting this imbalance through transcranial stimulation, deep-brain stimulation, or light-based therapy.
"In the meantime," said co-lead, "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."
http://newsroom.cumc.columbia.edu/blog/2017/01/19/in-alzheimers-excess-tau-protein-damages-brains-gps/
Excess tau protein damages brain's GPS in Alzheimer's
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