The mystery is starting to untangle. It has long been known that twisted fibres of a protein called tau collect in the brain cells of people with Alzheimer’s, but their exact role in the disease is unclear. Now a study in mice has shown how tau interferes with the strengthening of connections between neurons – the key mechanism by which we form memories.
In healthy cells, the tau protein helps to stabilise microtubules that act as rails for transporting materials around the cell. In people with Alzheimer’s, these proteins become toxic, but an important unanswered question is what forms of tau are toxic: the tangles may not be the whole story.
In the new study, Li Gan and her colleagues at the Gladstone Institute of Neurological Disease in San Francisco found that the brains of those with Alzheimer’s have high levels of tau with a particular modification, called acetylated tau.
They then looked at what acetylated tau does in a mouse model of Alzheimer’s, finding that it accumulates at synapses – the connections between neurons.
When we form memories, synapses become strengthened through extra receptors inserted into the cell membranes, and this heightens their response. But acetylated tau depletes another protein called KIBRA, which is essential for this synapse-strengthening mechanism.
“We’re excited because we think we now have a handle on the link between tau and memory,” says Gan. “We’re also cautious because we know this may not be the only link. It’s still early days in understanding the mechanism.”
In cultured neurons, restoring levels of KIBRA reversed the effects of acetylated tau, restoring their ability to strengthen connections. This offers a strategy for therapies, Gan says. “If we provide neurons with more of this protein, we can repair the lost synaptic strengthening that we usually observe.”
If synapses can’t become strengthened, the connections between neurons – and the memories they encode – may be lost. These lost synapses correlate more closely with cognitive decline than any other feature.
“It turns out that they’re very important – not just markers of cognitive change, but they may actually be driving the disease process in several ways,” says Tara Spires-Jones at the University of Edinburgh Medical School, a member of the grant review board at Alzheimer’s Research UK.
Spires-Jones cautions that findings in mouse studies have not always translated well to Alzheimer’s in humans. “I am really excited about this paper, and I think it is a good step in terms of knowing which the toxic forms of tau are and giving us new targets to follow up, but it is a long way from people.”
Journal reference: Neuron, DOI: 10.1016/j.neuron.2016.03.005
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