Tau tangles damage brain GPS in Alzheimer’s disease

Grandad got lost driving home, again. It’s often the first hint of Alzheimer’s disease.

Now a US team has pinpointed why this might happen. The brain’s so-called grid cells, which map your location like a personal GPS, are poisoned by abnormal clumps of a protein called tau.

The finding, published in Neuron today, offers a specific new test for the early stages of the disease and could be useful for testing new drugs. “It adds an interesting piece of the puzzle,” says Kevin Barnham, a neuroscientist at Australia’s Florey Institute of Neuroscience and Mental Health.

Alzheimer’s disease is like an unsolved murder mystery. For decades, researchers have been fingering two shady suspects: both of them disfigured proteins.

One is called beta amyloid. Normally soluble, the abnormal variety clumps between cells. The other potential culprit, tau, is also normally soluble; the disfigured form creates tangles inside cells.

Despite decades of research – and many failed drug trials – proving that either suspect was the cause of the disease, or figuring out just how they wreak their damage, has remained frustratingly difficult. “After 40 years, we have to rethink the disease in its entirety,” says Bryce Vissel, a neuroscientist at the University of Technology Sydney, Australia.

While beta amyloid has been the main suspect, most drugs aimed at clearing it away have had little effect in trials. The shift, now, is to anti-tau drugs.

In that context, the recent paper links early Alzheimer’s symptoms to tau’s actions in the brain. “We came from two ends and filled in the middle,” says study co-author Karen Duff from Columbia University. “It’s very satisfying.”

Post-mortem studies of Alzheimer’s patients show tau tangles appear in the brain sequentially. The first form in a region called the entorhinal cortex, a part of the brain involved in navigation.

Next affected is the hippocampus, crucial for making new memories, and finally the neocortex, associated with reasoning and language. 

The abnormal tau protein can travel between cells, seeding new tangles.

The researchers tried to model the sequence seen in humans by genetically engineering mice to produce an abnormal form of human tau in their entorhinal cortex.

The entorhinal cortex tissue contains various types of cells but those most affected by tau were the grid cells.

Co-author Abid Hussaini, also at Columbia University, inserted electrodes into those brain cells to measure their electrical characteristics.

Normally grid cells are highly excitable, but once the mice developed tau tangles at around 30 months of age, these cells became less active and eventually died.

At the same time, the mice began getting lost in their mazes.

It’s the first finding to highlight how grid cells are especially susceptible to the effects of tau, an effect “that may be unique to Alzheimer’s disease”, Duff says.

And that may offer a new model to test for drugs that target tau. “We’re always looking for a model that is relatable to the disease,” Barnham says, “and this effect on [grid cells] is potentially relatable.”